RBCC

Full text data of JAK2

JAK2 [Confidence: low (only semi-automatic identification from reviews)]
Tyrosine-protein kinase JAK2; 2.7.10.2 (Janus kinase 2; JAK-2)

UniProt O60674
ID JAK2_HUMAN Reviewed; 1132 AA.
AC O60674; O14636; O75297;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-JAN-2001, sequence version 2.
DT 22-JAN-2014, entry version 154.
DE RecName: Full=Tyrosine-protein kinase JAK2;
DE EC=2.7.10.2;
DE AltName: Full=Janus kinase 2;
DE Short=JAK-2;
GN Name=JAK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9618263; DOI=10.1006/bbrc.1998.8685;
RA Saltzman A., Stone M., Franks C., Searfoss G., Munro R., Jaye M.,
RA Ivashchenko Y.;
RT "Cloning and characterization of human Jak-2 kinase: high mRNA
RT expression in immune cells and muscle tissue.";
RL Biochem. Biophys. Res. Commun. 246:627-633(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9446644;
RA Dalal I., Arpaia E., Dadi H., Kulkarni S., Squire J., Roifman C.M.;
RT "Cloning and characterization of the human homolog of mouse Jak2.";
RL Blood 91:844-851(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND CHROMOSOMAL TRANSLOCATION WITH ETV6.
RX PubMed=9326218;
RA Peeters P., Raynaud S.D., Cools J., Wlodarska I., Grosgeorge J.,
RA Philip P., Monpoux F., Van Rompaey L., Baens M., Van Den Berghe H.,
RA Marynen P.;
RT "Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-
RT associated kinase JAK2 as a result of t(9;12) in a lymphoid and
RT t(9;15;12) in a myeloid leukemia.";
RL Blood 90:2535-2540(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [5]
RP INTERACTION WITH SKB1.
RX PubMed=10531356; DOI=10.1074/jbc.274.44.31531;
RA Pollack B.P., Kotenko S.V., He W., Izotova L.S., Barnoski B.L.,
RA Pestka S.;
RT "The human homologue of the yeast proteins Skb1 and Hsl7p interacts
RT with Jak kinases and contains protein methyltransferase activity.";
RL J. Biol. Chem. 274:31531-31542(1999).
RN [6]
RP INTERACTION WITH STAM2.
RC TISSUE=Fetal brain;
RX PubMed=10899310; DOI=10.1016/S0014-5793(00)01760-9;
RA Endo K., Takeshita T., Kasai H., Sasaki Y., Tanaka N., Asao H.,
RA Kikuchi K., Yamada M., Chenb M., O'Shea J.J., Sugamura K.;
RT "STAM2, a new member of the STAM family, binding to the Janus
RT kinases.";
RL FEBS Lett. 477:55-61(2000).
RN [7]
RP FUNCTION, AND INTERACTION WITH IL23R.
RX PubMed=12023369;
RA Parham C., Chirica M., Timans J., Vaisberg E., Travis M., Cheung J.,
RA Pflanz S., Zhang R., Singh K.P., Vega F., To W., Wagner J.,
RA O'Farrell A.-M., McClanahan T.K., Zurawski S., Hannum C., Gorman D.,
RA Rennick D.M., Kastelein R.A., de Waal Malefyt R., Moore K.W.;
RT "A receptor for the heterodimeric cytokine IL-23 is composed of IL-
RT 12Rbeta1 and a novel cytokine receptor subunit, IL-23R.";
RL J. Immunol. 168:5699-5708(2002).
RN [8]
RP CHROMOSOMAL TRANSLOCATION WITH PCM1.
RX PubMed=15805263; DOI=10.1158/0008-5472.CAN-04-4263;
RA Reiter A., Walz C., Watmore A., Schoch C., Blau I., Schlegelberger B.,
RA Berger U., Telford N., Aruliah S., Yin J.A., Vanstraelen D.,
RA Barker H.F., Taylor P.C., O'Driscoll A., Benedetti F., Rudolph C.,
RA Kolb H.-J., Hochhaus A., Hehlmann R., Chase A., Cross N.C.P.;
RT "The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute
RT leukemia that fuses PCM1 to JAK2.";
RL Cancer Res. 65:2662-2667(2005).
RN [9]
RP CHROMOSOMAL TRANSLOCATION WITH PCM1.
RX PubMed=16034466; DOI=10.1038/sj.leu.2403879;
RA Murati A., Gelsi-Boyer V., Adelaide J., Perot C., Talmant P.,
RA Giraudier S., Lode L., Letessier A., Delaval B., Brunel V., Imbert M.,
RA Garand R., Xerri L., Birnbaum D., Mozziconacci M.-J., Chaffanet M.;
RT "PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid
RT leukemia with t(8;9) translocation.";
RL Leukemia 19:1692-1696(2005).
RN [10]
RP CHROMOSOMAL TRANSLOCATION WITH PCM1.
RX PubMed=16091753; DOI=10.1038/sj.onc.1208850;
RA Bousquet M., Quelen C., De Mas V., Duchayne E., Roquefeuil B.,
RA Delsol G., Laurent G., Dastugue N., Brousset P.;
RT "The t(8;9)(p22;p24) translocation in atypical chronic myeloid
RT leukaemia yields a new PCM1-JAK2 fusion gene.";
RL Oncogene 24:7248-7252(2005).
RN [11]
RP CHROMOSOMAL TRANSLOCATION WITH PCM1.
RX PubMed=16769584;
RA Bacher U., Reiter A., Haferlach T., Mueller L., Schnittger S.,
RA Kern W., Schoch C.;
RT "A combination of cytomorphology, cytogenetic analysis, fluorescence
RT in situ hybridization and reverse transcriptase polymerase chain
RT reaction for establishing clonality in cases of persisting
RT hypereosinophilia.";
RL Haematologica 91:817-820(2006).
RN [12]
RP TISSUE SPECIFICITY, AND CHROMOSOMAL TRANSLOCATION WITH PCM1.
RX PubMed=16424865; DOI=10.1038/sj.leu.2404104;
RA Adelaide J., Perot C., Gelsi-Boyer V., Pautas C., Murati A.,
RA Copie-Bergman C., Imbert M., Chaffanet M., Birnbaum D.,
RA Mozziconacci M.-J.;
RT "A t(8;9) translocation with PCM1-JAK2 fusion in a patient with T-cell
RT lymphoma.";
RL Leukemia 20:536-537(2006).
RN [13]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19783980; DOI=10.1038/nature08448;
RA Dawson M.A., Bannister A.J., Gottgens B., Foster S.D., Bartke T.,
RA Green A.R., Kouzarides T.;
RT "JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from
RT chromatin.";
RL Nature 461:819-822(2009).
RN [14]
RP ENZYME REGULATION.
RX PubMed=21036157; DOI=10.1016/j.bbrc.2010.10.101;
RA Yao X., Balamurugan P., Arvey A., Leslie C., Zhang L.;
RT "Heme controls the regulation of protein tyrosine kinases Jak2 and
RT Src.";
RL Biochem. Biophys. Res. Commun. 403:30-35(2010).
RN [15]
RP FUNCTION.
RX PubMed=20098430; DOI=10.1038/nm.2079;
RA Guilluy C., Bregeon J., Toumaniantz G., Rolli-Derkinderen M.,
RA Retailleau K., Loufrani L., Henrion D., Scalbert E., Bril A.,
RA Torres R.M., Offermanns S., Pacaud P., Loirand G.;
RT "The Rho exchange factor Arhgef1 mediates the effects of angiotensin
RT II on vascular tone and blood pressure.";
RL Nat. Med. 16:183-190(2010).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF CDKN1B.
RX PubMed=21423214; DOI=10.1038/onc.2011.68;
RA Jakel H., Weinl C., Hengst L.;
RT "Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor
RT signaling to cell cycle control.";
RL Oncogene 30:3502-3512(2011).
RN [17]
RP REVIEW ON FUNCTION.
RX PubMed=16456223; DOI=10.1385/CBB:44:2:213;
RA Wallace T.A., Sayeski P.P.;
RT "Jak2 tyrosine kinase: a mediator of both housekeeping and ligand-
RT dependent gene expression?";
RL Cell Biochem. Biophys. 44:213-222(2006).
RN [18]
RP REVIEW ON FUNCTION.
RX PubMed=19290934; DOI=10.1111/j.1600-065X.2008.00754.x;
RA Ghoreschi K., Laurence A., O'Shea J.J.;
RT "Janus kinases in immune cell signaling.";
RL Immunol. Rev. 228:273-287(2009).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 840-1132 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR, MASS SPECTROMETRY, AND PHOSPHORYLATION AT
RP TYR-1007 AND TYR-1008.
RX PubMed=16174768; DOI=10.1182/blood-2005-06-2413;
RA Lucet I.S., Fantino E., Styles M., Bamert R., Patel O.,
RA Broughton S.E., Walter M., Burns C.J., Treutlein H., Wilks A.F.,
RA Rossjohn J.;
RT "The structural basis of Janus kinase 2 inhibition by a potent and
RT specific pan-Janus kinase inhibitor.";
RL Blood 107:176-183(2006).
RN [20]
RP VARIANT PV PHE-617.
RX PubMed=15781101; DOI=10.1016/S0140-6736(05)71142-9;
RG The cancer genome project;
RA Baxter E.J., Scott L.M., Campbell P.J., East C., Fourouclas N.,
RA Swanton S., Vassiliou G.S., Bench A.J., Boyd E.M., Curtin N.,
RA Scott M.A., Erber W.N., Green A.R.;
RT "Acquired mutation of the tyrosine kinase JAK2 in human
RT myeloproliferative disorders.";
RL Lancet 365:1054-1061(2005).
RN [21]
RP ERRATUM.
RG The cancer genome project;
RA Baxter E.J., Scott L.M., Campbell P.J., East C., Fourouclas N.,
RA Swanton S., Vassiliou G.S., Bench A.J., Boyd E.M., Curtin N.,
RA Scott M.A., Erber W.N., Green A.R.;
RL Lancet 366:122-122(2005).
RN [22]
RP VARIANT THCYT3 PHE-617.
RX PubMed=16325696; DOI=10.1016/S0140-6736(05)67785-9;
RG The United Kingdom myeloproliferative disorders study group;
RG The medical research council adult leukaemia working party;
RG The Australasian leukaemia and lymphoma group;
RA Campbell P.J., Scott L.M., Buck G., Wheatley K., East C.L.,
RA Marsden J.T., Duffy A., Boyd E.M., Bench A.J., Scott M.A.,
RA Vassiliou G.S., Milligan D.W., Smith S.R., Erber W.N., Bareford D.,
RA Wilkins B.S., Reilly J.T., Harrison C.N., Green A.R.;
RT "Definition of subtypes of essential thrombocythaemia and relation to
RT polycythaemia vera based on JAK2 V617F mutation status: a prospective
RT study.";
RL Lancet 366:1945-1953(2005).
RN [23]
RP VARIANT PV PHE-617, AND CHARACTERIZATION OF VARIANT PV PHE-617.
RX PubMed=15793561; DOI=10.1038/nature03546;
RA James C., Ugo V., Le Couedic J.-P., Staerk J., Delhommeau F.,
RA Lacout C., Garcon L., Raslova H., Berger R., Bennaceur-Griscelli A.,
RA Villeval J.L., Constantinescu S.N., Casadevall N., Vainchenker W.;
RT "A unique clonal JAK2 mutation leading to constitutive signalling
RT causes polycythaemia vera.";
RL Nature 434:1144-1148(2005).
RN [24]
RP VARIANT PV PHE-617.
RX PubMed=15858187; DOI=10.1056/NEJMoa051113;
RA Kralovics R., Passamonti F., Buser A.S., Teo S.-S., Tiedt R.,
RA Passweg J.R., Tichelli A., Cazzola M., Skoda R.C.;
RT "A gain-of-function mutation of JAK2 in myeloproliferative
RT disorders.";
RL N. Engl. J. Med. 352:1779-1790(2005).
RN [25]
RP ASSOCIATION OF VARIANT PHE-617 WITH SUSCEPTIBILITY BUDD-CHIARI
RP SYNDROME.
RX PubMed=16707754; DOI=10.1056/NEJMcpc069006;
RA Chung R.T., Iafrate A.J., Amrein P.C., Sahani D.V., Misdraji J.;
RT "Case records of the Massachusetts General Hospital. Case 15-2006: a
RT 46-year-old woman with sudden onset of abdominal distention.";
RL N. Engl. J. Med. 354:2166-2175(2006).
RN [26]
RP VARIANTS AML ASN-607 AND PHE-617.
RX PubMed=16247455; DOI=10.1038/sj.onc.1209163;
RA Lee J.W., Kim Y.G., Soung Y.H., Han K.J., Kim S.Y., Rhim H.S.,
RA Min W.S., Nam S.W., Park W.S., Lee J.Y., Yoo N.J., Lee S.H.;
RT "The JAK2 V617F mutation in de novo acute myelogenous leukemias.";
RL Oncogene 25:1434-1436(2006).
RN [27]
RP VARIANT PV PHE-617.
RX PubMed=16603627; DOI=10.1073/pnas.0601462103;
RA Jamieson C.H.M., Gotlib J., Durocher J.A., Chao M.P., Mariappan M.R.,
RA Lay M., Jones C., Zehnder J.L., Lilleberg S.L., Weissman I.L.;
RT "The JAK2 V617F mutation occurs in hematopoietic stem cells in
RT polycythemia vera and predisposes toward erythroid differentiation.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:6224-6229(2006).
RN [28]
RP VARIANTS MYELOPROLIFERATIVE DISORDER WITH ERYTHROCYTOSIS
RP 537-PHE--LYS-539 DELINS LEU; 538-GLN-LEU-539 AND LEU-539.
RX PubMed=17267906; DOI=10.1056/NEJMoa065202;
RA Scott L.M., Tong W., Levine R.L., Scott M.A., Beer P.A.,
RA Stratton M.R., Futreal P.A., Erber W.N., McMullin M.F., Harrison C.N.,
RA Warren A.J., Gilliland D.G., Lodish H.F., Green A.R.;
RT "JAK2 exon 12 mutations in polycythemia vera and idiopathic
RT erythrocytosis.";
RL N. Engl. J. Med. 356:459-468(2007).
RN [29]
RP VARIANTS [LARGE SCALE ANALYSIS] ASP-127; GLN-191; ARG-346; GLU-377;
RP VAL-393 AND HIS-1063.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [30]
RP VARIANT THCYT3 ILE-617.
RX PubMed=22397670; DOI=10.1056/NEJMc1200349;
RA Mead A.J., Rugless M.J., Jacobsen S.E., Schuh A.;
RT "Germline JAK2 mutation in a family with hereditary thrombocytosis.";
RL N. Engl. J. Med. 366:967-969(2012).
CC -!- FUNCTION: Non-receptor tyrosine kinase involved in various
CC processes such as cell growth, development, differentiation or
CC histone modifications. Mediates essential signaling events in both
CC innate and adaptive immunity. In the cytoplasm, plays a pivotal
CC role in signal transduction via its association with type I
CC receptors such as growth hormone (GHR), prolactin (PRLR), leptin
CC (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II
CC receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple
CC interleukins. Following ligand-binding to cell surface receptors,
CC phosphorylates specific tyrosine residues on the cytoplasmic tails
CC of the receptor, creating docking sites for STATs proteins.
CC Subsequently, phosphorylates the STATs proteins once they are
CC recruited to the receptor. Phosphorylated STATs then form
CC homodimer or heterodimers and translocate to the nucleus to
CC activate gene transcription. For example, cell stimulation with
CC erythropoietin (EPO) during erythropoiesis leads to JAK2
CC autophosphorylation, activation, and its association with
CC erythropoietin receptor (EPOR) that becomes phosphorylated in its
CC cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited,
CC phosphorylated and activated by JAK2. Once activated, dimerized
CC STAT5 translocates into the nucleus and promotes the transcription
CC of several essential genes involved in the modulation of
CC erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced
CC ARHGEF1 phosphorylation. Plays a role in cell cycle by
CC phosphorylating CDKN1B. Cooperates with TEC through reciprocal
CC phosphorylation to mediate cytokine-driven activation of FOS
CC transcription. In the nucleus, plays a key role in chromatin by
CC specifically mediating phosphorylation of 'Tyr-41' of histone H3
CC (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1
CC alpha) from chromatin.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- ENZYME REGULATION: Regulated by autophosphorylation, can both
CC activate or decrease activity (By similarity). Heme regulates its
CC activity by enhancing the phosphorylation on Tyr-1007 and Tyr-
CC 1008.
CC -!- SUBUNIT: Interacts with EPOR, LYN, SIRPA, SH2B1 and TEC (By
CC similarity). Interacts with IL23R, SKB1 and STAM2.
CC -!- INTERACTION:
CC P32927:CSF2RB; NbExp=4; IntAct=EBI-518647, EBI-1809771;
CC P16333:NCK1; NbExp=2; IntAct=EBI-518647, EBI-389883;
CC P18031:PTPN1; NbExp=5; IntAct=EBI-518647, EBI-968788;
CC -!- SUBCELLULAR LOCATION: Endomembrane system; Peripheral membrane
CC protein (By similarity). Cytoplasm. Nucleus.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed throughout most
CC tissues.
CC -!- DOMAIN: Possesses 2 protein kinase domains. The second one
CC probably contains the catalytic domain, while the presence of
CC slight differences suggest a different role for protein kinase 1
CC (By similarity).
CC -!- PTM: Autophosphorylated, leading to regulate its activity. Leptin
CC promotes phosphorylation on tyrosine residues, including
CC phosphorylation on Tyr-813. Autophosphorylation on Tyr-119 in
CC response to EPO down-regulates its kinase activity.
CC Autophosphorylation on Tyr-868, Tyr-966 and Tyr-972 in response to
CC growth hormone (GH) are required for maximal kinase activity. Also
CC phosphorylated by TEC (By similarity).
CC -!- DISEASE: Note=Chromosomal aberrations involving JAK2 are found in
CC both chronic and acute forms of eosinophilic, lymphoblastic and
CC myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links
CC the protein kinase domain of JAK2 to the major portion of PCM1.
CC Translocation t(9;12)(p24;p13) with ETV6.
CC -!- DISEASE: Budd-Chiari syndrome (BDCHS) [MIM:600880]: A syndrome
CC caused by obstruction of hepatic venous outflow involving either
CC the hepatic veins or the terminal segment of the inferior vena
CC cava. Obstructions are generally caused by thrombosis and lead to
CC hepatic congestion and ischemic necrosis. Clinical manifestations
CC observed in the majority of patients include hepatomegaly, right
CC upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is
CC associated with a combination of disease states including primary
CC myeloproliferative syndromes and thrombophilia due to factor V
CC Leiden, protein C deficiency and antithrombin III deficiency.
CC Budd-Chiari syndrome is a rare but typical complication in
CC patients with polycythemia vera. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Polycythemia vera (PV) [MIM:263300]: A myeloproliferative
CC disorder characterized by abnormal proliferation of all
CC hematopoietic bone marrow elements, erythroid hyperplasia, an
CC absolute increase in total blood volume, but also by myeloid
CC leukocytosis, thrombocytosis and splenomegaly. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Thrombocythemia 3 (THCYT3) [MIM:614521]: A
CC myeloproliferative disorder characterized by excessive platelet
CC production, resulting in increased numbers of circulating
CC platelets. It can be associated with spontaneous hemorrhages and
CC thrombotic episodes. Note=The disease may be caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Myelofibrosis (MYELOF) [MIM:254450]: A disorder
CC characterized by replacement of the bone marrow by fibrous tissue,
CC occurring in association with a myeloproliferative disorder.
CC Clinical manifestations may include anemia, pallor, splenomegaly,
CC hypermetabolic state, petechiae, ecchymosis, bleeding,
CC lymphadenopathy, hepatomegaly, portal hypertension. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype
CC of acute leukemia, a cancer of the white blood cells. AML is a
CC malignant disease of bone marrow characterized by maturational
CC arrest of hematopoietic precursors at an early stage of
CC development. Clonal expansion of myeloid blasts occurs in bone
CC marrow, blood, and other tissue. Myelogenous leukemias develop
CC from changes in cells that normally produce neutrophils,
CC basophils, eosinophils and monocytes. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. JAK subfamily.
CC -!- SIMILARITY: Contains 1 FERM domain.
CC -!- SIMILARITY: Contains 2 protein kinase domains.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/JAK98.html";
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DR EMBL; AF058925; AAC23982.1; -; mRNA.
DR EMBL; AF001362; AAC23653.1; -; mRNA.
DR EMBL; AF005216; AAB82092.1; -; mRNA.
DR EMBL; AL161450; CAD13329.1; -; Genomic_DNA.
DR PIR; JW0091; JW0091.
DR RefSeq; NP_004963.1; NM_004972.3.
DR RefSeq; XP_005251512.1; XM_005251455.1.
DR UniGene; Hs.656213; -.
DR PDB; 2B7A; X-ray; 2.00 A; A/B=840-1132.
DR PDB; 2W1I; X-ray; 2.60 A; A/B=835-1132.
DR PDB; 2XA4; X-ray; 2.04 A; A/B=835-1132.
DR PDB; 3E62; X-ray; 1.92 A; A=839-1131.
DR PDB; 3E63; X-ray; 1.90 A; A=839-1131.
DR PDB; 3E64; X-ray; 1.80 A; A=839-1131.
DR PDB; 3FUP; X-ray; 2.40 A; A/B=840-1132.
DR PDB; 3IO7; X-ray; 2.60 A; A=842-1132.
DR PDB; 3IOK; X-ray; 2.10 A; A=842-1132.
DR PDB; 3JY9; X-ray; 2.10 A; A=842-1130.
DR PDB; 3KCK; X-ray; 2.20 A; A=842-1132.
DR PDB; 3KRR; X-ray; 1.80 A; A=840-1132.
DR PDB; 3LPB; X-ray; 2.00 A; A/B=840-1132.
DR PDB; 3Q32; X-ray; 2.50 A; A/B=839-1132.
DR PDB; 3RVG; X-ray; 2.50 A; A=835-1132.
DR PDB; 3TJC; X-ray; 2.40 A; A/B=837-1132.
DR PDB; 3TJD; X-ray; 2.90 A; A/B=837-1132.
DR PDB; 3UGC; X-ray; 1.34 A; A=840-1132.
DR PDB; 3ZMM; X-ray; 2.51 A; A/B=835-1132.
DR PDB; 4AQC; X-ray; 1.90 A; A/B=835-1132.
DR PDB; 4BBE; X-ray; 1.90 A; A/B/C/D=839-1132.
DR PDB; 4BBF; X-ray; 2.00 A; A/B/C/D=839-1132.
DR PDB; 4E4M; X-ray; 2.25 A; A/B/D/E=833-1132.
DR PDB; 4E6D; X-ray; 2.22 A; A/B=835-1132.
DR PDB; 4E6Q; X-ray; 1.95 A; A/B=835-1132.
DR PDB; 4F08; X-ray; 2.82 A; A/B=833-1132.
DR PDB; 4F09; X-ray; 2.40 A; A=833-1132.
DR PDB; 4FVP; X-ray; 2.01 A; A=536-812.
DR PDB; 4FVQ; X-ray; 1.75 A; A=536-812.
DR PDB; 4FVR; X-ray; 2.00 A; A=536-812.
DR PDB; 4GFM; X-ray; 2.30 A; A=833-1132.
DR PDB; 4GMY; X-ray; 2.40 A; A=833-1132.
DR PDB; 4HGE; X-ray; 2.30 A; A/B=833-1132.
DR PDB; 4IVA; X-ray; 1.50 A; A=833-1132.
DR PDB; 4JI9; X-ray; 2.40 A; A/B=833-1132.
DR PDB; 4JIA; X-ray; 1.85 A; A=833-1132.
DR PDBsum; 2B7A; -.
DR PDBsum; 2W1I; -.
DR PDBsum; 2XA4; -.
DR PDBsum; 3E62; -.
DR PDBsum; 3E63; -.
DR PDBsum; 3E64; -.
DR PDBsum; 3FUP; -.
DR PDBsum; 3IO7; -.
DR PDBsum; 3IOK; -.
DR PDBsum; 3JY9; -.
DR PDBsum; 3KCK; -.
DR PDBsum; 3KRR; -.
DR PDBsum; 3LPB; -.
DR PDBsum; 3Q32; -.
DR PDBsum; 3RVG; -.
DR PDBsum; 3TJC; -.
DR PDBsum; 3TJD; -.
DR PDBsum; 3UGC; -.
DR PDBsum; 3ZMM; -.
DR PDBsum; 4AQC; -.
DR PDBsum; 4BBE; -.
DR PDBsum; 4BBF; -.
DR PDBsum; 4E4M; -.
DR PDBsum; 4E6D; -.
DR PDBsum; 4E6Q; -.
DR PDBsum; 4F08; -.
DR PDBsum; 4F09; -.
DR PDBsum; 4FVP; -.
DR PDBsum; 4FVQ; -.
DR PDBsum; 4FVR; -.
DR PDBsum; 4GFM; -.
DR PDBsum; 4GMY; -.
DR PDBsum; 4HGE; -.
DR PDBsum; 4IVA; -.
DR PDBsum; 4JI9; -.
DR PDBsum; 4JIA; -.
DR ProteinModelPortal; O60674; -.
DR SMR; O60674; 401-1132.
DR DIP; DIP-33880N; -.
DR IntAct; O60674; 22.
DR MINT; MINT-158048; -.
DR STRING; 9606.ENSP00000371067; -.
DR BindingDB; O60674; -.
DR ChEMBL; CHEMBL2971; -.
DR GuidetoPHARMACOLOGY; 2048; -.
DR PhosphoSite; O60674; -.
DR PaxDb; O60674; -.
DR PRIDE; O60674; -.
DR DNASU; 3717; -.
DR Ensembl; ENST00000381652; ENSP00000371067; ENSG00000096968.
DR Ensembl; ENST00000539801; ENSP00000440387; ENSG00000096968.
DR GeneID; 3717; -.
DR KEGG; hsa:3717; -.
DR UCSC; uc003ziw.3; human.
DR CTD; 3717; -.
DR GeneCards; GC09P004985; -.
DR HGNC; HGNC:6192; JAK2.
DR HPA; CAB013089; -.
DR MIM; 147796; gene.
DR MIM; 254450; phenotype.
DR MIM; 263300; phenotype.
DR MIM; 600880; phenotype.
DR MIM; 601626; phenotype.
DR MIM; 614521; phenotype.
DR neXtProt; NX_O60674; -.
DR Orphanet; 131; Budd-Chiari syndrome.
DR Orphanet; 3318; Essential thrombocythemia.
DR Orphanet; 71493; Familial thrombocytosis.
DR Orphanet; 824; Myelofibrosis with myeloid metaplasia.
DR Orphanet; 729; Polycythemia vera.
DR PharmGKB; PA29989; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000049158; -.
DR HOVERGEN; HBG006195; -.
DR InParanoid; O60674; -.
DR KO; K04447; -.
DR OMA; CHGPISM; -.
DR OrthoDB; EOG7BW0HM; -.
DR PhylomeDB; O60674; -.
DR BRENDA; 2.7.10.2; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; O60674; -.
DR ChiTaRS; JAK2; human.
DR EvolutionaryTrace; O60674; -.
DR GeneWiki; Janus_kinase_2; -.
DR GenomeRNAi; 3717; -.
DR NextBio; 14567; -.
DR PRO; PR:O60674; -.
DR ArrayExpress; O60674; -.
DR Bgee; O60674; -.
DR CleanEx; HS_JAK2; -.
DR Genevestigator; O60674; -.
DR GO; GO:0005901; C:caveola; ISS:BHF-UCL.
DR GO; GO:0005856; C:cytoskeleton; IEA:InterPro.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0012505; C:endomembrane system; IEA:UniProtKB-SubCell.
DR GO; GO:0031904; C:endosome lumen; TAS:Reactome.
DR GO; GO:0016363; C:nuclear matrix; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005131; F:growth hormone receptor binding; ISS:BHF-UCL.
DR GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR GO; GO:0042393; F:histone binding; IDA:UniProtKB.
DR GO; GO:0035401; F:histone kinase activity (H3-Y41 specific); IDA:UniProtKB.
DR GO; GO:0005143; F:interleukin-12 receptor binding; ISS:BHF-UCL.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0019901; F:protein kinase binding; IDA:BHF-UCL.
DR GO; GO:0030041; P:actin filament polymerization; NAS:BHF-UCL.
DR GO; GO:0097296; P:activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway; ISS:BHF-UCL.
DR GO; GO:0042977; P:activation of JAK2 kinase activity; ISS:UniProtKB.
DR GO; GO:0000186; P:activation of MAPKK activity; IEA:Ensembl.
DR GO; GO:0031103; P:axon regeneration; IEA:Ensembl.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0006928; P:cellular component movement; TAS:ProtInc.
DR GO; GO:0030218; P:erythrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISS:BHF-UCL.
DR GO; GO:0007186; P:G-protein coupled receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0035722; P:interleukin-12-mediated signaling pathway; IDA:BHF-UCL.
DR GO; GO:0008631; P:intrinsic apoptotic signaling pathway in response to oxidative stress; IEA:Ensembl.
DR GO; GO:0060397; P:JAK-STAT cascade involved in growth hormone signaling pathway; ISS:UniProtKB.
DR GO; GO:0061180; P:mammary gland epithelium development; ISS:BHF-UCL.
DR GO; GO:0007498; P:mesoderm development; TAS:ProtInc.
DR GO; GO:0031959; P:mineralocorticoid receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; ISS:BHF-UCL.
DR GO; GO:0022408; P:negative regulation of cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0043392; P:negative regulation of DNA binding; ISS:BHF-UCL.
DR GO; GO:0045822; P:negative regulation of heart contraction; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048008; P:platelet-derived growth factor receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0050867; P:positive regulation of cell activation; IEA:Ensembl.
DR GO; GO:0045597; P:positive regulation of cell differentiation; IEA:Ensembl.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0010811; P:positive regulation of cell-substrate adhesion; IDA:BHF-UCL.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IEA:Ensembl.
DR GO; GO:0043388; P:positive regulation of DNA binding; IEA:Ensembl.
DR GO; GO:0060399; P:positive regulation of growth hormone receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IEA:Ensembl.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Ensembl.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IEA:Ensembl.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISS:BHF-UCL.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; ISS:BHF-UCL.
DR GO; GO:0032516; P:positive regulation of phosphoprotein phosphatase activity; IEA:Ensembl.
DR GO; GO:0033160; P:positive regulation of protein import into nucleus, translocation; IEA:Ensembl.
DR GO; GO:0051091; P:positive regulation of sequence-specific DNA binding transcription factor activity; IEA:Ensembl.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:BHF-UCL.
DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; ISS:UniProtKB.
DR GO; GO:0042523; P:positive regulation of tyrosine phosphorylation of Stat5 protein; ISS:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IDA:BHF-UCL.
DR GO; GO:0060334; P:regulation of interferon-gamma-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0046677; P:response to antibiotic; IDA:MGI.
DR GO; GO:0033194; P:response to hydroperoxide; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISS:BHF-UCL.
DR GO; GO:0007262; P:STAT protein import into nucleus; ISS:BHF-UCL.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IDA:BHF-UCL.
DR GO; GO:0007260; P:tyrosine phosphorylation of STAT protein; ISS:BHF-UCL.
DR GO; GO:0042508; P:tyrosine phosphorylation of Stat1 protein; IEA:Ensembl.
DR GO; GO:0042503; P:tyrosine phosphorylation of Stat3 protein; IEA:Ensembl.
DR GO; GO:0042506; P:tyrosine phosphorylation of Stat5 protein; IEA:Ensembl.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR019748; FERM_central.
DR InterPro; IPR000299; FERM_domain.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016251; Tyr_kinase_non-rcpt_Jak/Tyk2.
DR InterPro; IPR020693; Tyr_kinase_non-rcpt_Jak2.
DR Pfam; PF07714; Pkinase_Tyr; 2.
DR Pfam; PF00017; SH2; 1.
DR PIRSF; PIRSF000636; TyrPK_Jak; 1.
DR PRINTS; PR01823; JANUSKINASE.
DR PRINTS; PR01825; JANUSKINASE2.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00295; B41; 1.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00219; TyrKc; 2.
DR SUPFAM; SSF47031; SSF47031; 1.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS00660; FERM_1; FALSE_NEG.
DR PROSITE; PS00661; FERM_2; FALSE_NEG.
DR PROSITE; PS50057; FERM_3; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 2.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Adaptive immunity; ATP-binding; Chromatin regulator;
KW Chromosomal rearrangement; Complete proteome; Cytoplasm;
KW Disease mutation; Immunity; Innate immunity; Kinase; Membrane;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Proto-oncogene; Reference proteome; Repeat; SH2 domain; Transferase;
KW Tyrosine-protein kinase.
FT CHAIN 1 1132 Tyrosine-protein kinase JAK2.
FT /FTId=PRO_0000088112.
FT DOMAIN 37 380 FERM.
FT DOMAIN 401 482 SH2; atypical.
FT DOMAIN 545 809 Protein kinase 1.
FT DOMAIN 849 1124 Protein kinase 2.
FT NP_BIND 855 863 ATP (By similarity).
FT REGION 1 239 Interaction with
FT cytokine/interferon/growth hormone
FT receptors (By similarity).
FT ACT_SITE 976 976 Proton acceptor (By similarity).
FT BINDING 882 882 ATP (By similarity).
FT SITE 352 353 Breakpoint for translocation to form
FT PCM1-JAK2 fusion protein.
FT SITE 442 443 Breakpoint for translocation to form
FT PCM1-JAK2 fusion protein.
FT SITE 450 451 Breakpoint for translocation to form
FT PCM1-JAK2 fusion protein.
FT SITE 504 505 Breakpoint for translocation to form
FT PCM1-JAK2 fusion protein.
FT SITE 710 711 Breakpoint for translocation to form
FT PCM1-JAK2 fusion protein.
FT MOD_RES 119 119 Phosphotyrosine; by autocatalysis (By
FT similarity).
FT MOD_RES 372 372 Phosphotyrosine (By similarity).
FT MOD_RES 373 373 Phosphotyrosine (By similarity).
FT MOD_RES 523 523 Phosphoserine (By similarity).
FT MOD_RES 813 813 Phosphotyrosine (By similarity).
FT MOD_RES 868 868 Phosphotyrosine; by autocatalysis (By
FT similarity).
FT MOD_RES 966 966 Phosphotyrosine; by autocatalysis (By
FT similarity).
FT MOD_RES 972 972 Phosphotyrosine; by autocatalysis (By
FT similarity).
FT MOD_RES 1007 1007 Phosphotyrosine; by autocatalysis.
FT MOD_RES 1008 1008 Phosphotyrosine; by autocatalysis
FT (Probable).
FT VARIANT 127 127 G -> D (in dbSNP:rs56118985).
FT /FTId=VAR_041716.
FT VARIANT 191 191 K -> Q (in an ovarian serous carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041717.
FT VARIANT 346 346 K -> R (in dbSNP:rs55667734).
FT /FTId=VAR_041718.
FT VARIANT 377 377 A -> E (in dbSNP:rs55953208).
FT /FTId=VAR_041719.
FT VARIANT 393 393 L -> V (in dbSNP:rs2230723).
FT /FTId=VAR_041720.
FT VARIANT 537 539 FHK -> L (in myeloproliferative disorder
FT with erythrocytosis).
FT /FTId=VAR_032693.
FT VARIANT 538 539 HK -> QL (in myeloproliferative disorder
FT with erythrocytosis).
FT /FTId=VAR_032694.
FT VARIANT 539 539 K -> L (in myeloproliferative disorder
FT with erythrocytosis; requires 2
FT nucleotide substitutions).
FT /FTId=VAR_032695.
FT VARIANT 584 584 D -> E (in dbSNP:rs17490221).
FT /FTId=VAR_043129.
FT VARIANT 607 607 K -> N (in AML).
FT /FTId=VAR_032696.
FT VARIANT 617 617 V -> F (in PV, THCYT3 and AML; associated
FT with susceptibility to Budd-Chiari
FT syndrome; somatic mutation in a high
FT percentage of patients with essential
FT thrombocythemia or myelofibrosis; leads
FT to constitutive tyrosine phosphorylation
FT activity that promotes cytokine
FT hypersensitivity).
FT /FTId=VAR_032697.
FT VARIANT 617 617 V -> I (in THCYT3).
FT /FTId=VAR_067534.
FT VARIANT 1063 1063 R -> H (in dbSNP:rs41316003).
FT /FTId=VAR_041721.
FT CONFLICT 321 321 P -> S (in Ref. 1; AAC23982).
FT CONFLICT 1126 1126 I -> V (in Ref. 2; AAC23653).
FT HELIX 542 544
FT STRAND 545 554
FT STRAND 557 567
FT HELIX 569 571
FT STRAND 573 583
FT HELIX 585 590
FT HELIX 591 602
FT STRAND 612 616
FT STRAND 623 627
FT HELIX 634 640
FT HELIX 642 644
FT HELIX 647 666
FT HELIX 676 678
FT STRAND 679 683
FT HELIX 687 689
FT STRAND 694 697
FT TURN 704 706
FT HELIX 709 714
FT TURN 715 718
FT HELIX 721 725
FT HELIX 727 729
FT HELIX 732 747
FT TURN 748 750
FT TURN 753 756
FT HELIX 759 767
FT HELIX 781 787
FT HELIX 792 794
FT HELIX 798 806
FT STRAND 836 838
FT HELIX 846 848
FT STRAND 849 857
FT STRAND 859 868
FT STRAND 872 874
FT STRAND 877 885
FT HELIX 889 903
FT STRAND 913 917
FT HELIX 919 922
FT STRAND 926 930
FT HELIX 937 943
FT HELIX 945 947
FT HELIX 950 969
FT HELIX 979 981
FT STRAND 982 986
FT STRAND 989 992
FT HELIX 995 997
FT STRAND 1006 1009
FT HELIX 1017 1020
FT HELIX 1023 1028
FT STRAND 1030 1032
FT HELIX 1033 1049
FT HELIX 1053 1055
FT HELIX 1057 1065
FT HELIX 1072 1083
FT HELIX 1096 1105
FT HELIX 1110 1112
FT HELIX 1116 1128
SQ SEQUENCE 1132 AA; 130674 MW; C30669EF1A7DA80C CRC64;
MGMACLTMTE MEGTSTSSIY QNGDISGNAN SMKQIDPVLQ VYLYHSLGKS EADYLTFPSG
EYVAEEICIA ASKACGITPV YHNMFALMSE TERIWYPPNH VFHIDESTRH NVLYRIRFYF
PRWYCSGSNR AYRHGISRGA EAPLLDDFVM SYLFAQWRHD FVHGWIKVPV THETQEECLG
MAVLDMMRIA KENDQTPLAI YNSISYKTFL PKCIRAKIQD YHILTRKRIR YRFRRFIQQF
SQCKATARNL KLKYLINLET LQSAFYTEKF EVKEPGSGPS GEEIFATIII TGNGGIQWSR
GKHKESETLT EQDLQLYCDF PNIIDVSIKQ ANQEGSNESR VVTIHKQDGK NLEIELSSLR
EALSFVSLID GYYRLTADAH HYLCKEVAPP AVLENIQSNC HGPISMDFAI SKLKKAGNQT
GLYVLRCSPK DFNKYFLTFA VERENVIEYK HCLITKNENE EYNLSGTKKN FSSLKDLLNC
YQMETVRSDN IIFQFTKCCP PKPKDKSNLL VFRTNGVSDV PTSPTLQRPT HMNQMVFHKI
RNEDLIFNES LGQGTFTKIF KGVRREVGDY GQLHETEVLL KVLDKAHRNY SESFFEAASM
MSKLSHKHLV LNYGVCVCGD ENILVQEFVK FGSLDTYLKK NKNCINILWK LEVAKQLAWA
MHFLEENTLI HGNVCAKNIL LIREEDRKTG NPPFIKLSDP GISITVLPKD ILQERIPWVP
PECIENPKNL NLATDKWSFG TTLWEICSGG DKPLSALDSQ RKLQFYEDRH QLPAPKWAEL
ANLINNCMDY EPDFRPSFRA IIRDLNSLFT PDYELLTEND MLPNMRIGAL GFSGAFEDRD
PTQFEERHLK FLQQLGKGNF GSVEMCRYDP LQDNTGEVVA VKKLQHSTEE HLRDFEREIE
ILKSLQHDNI VKYKGVCYSA GRRNLKLIME YLPYGSLRDY LQKHKERIDH IKLLQYTSQI
CKGMEYLGTK RYIHRDLATR NILVENENRV KIGDFGLTKV LPQDKEYYKV KEPGESPIFW
YAPESLTESK FSVASDVWSF GVVLYELFTY IEKSKSPPAE FMRMIGNDKQ GQMIVFHLIE
LLKNNGRLPR PDGCPDEIYM IMTECWNNNV NQRPSFRDLA LRVDQIRDNM AG
//

MIM 147796
*RECORD*
*FIELD* NO
147796
*FIELD* TI
*147796 JANUS KINASE 2; JAK2
JAK2/ETV6 FUSION GENE, INCLUDED
*FIELD* TX

DESCRIPTION
read more
JAK2 kinase is a member of a family of tyrosine kinases involved in
cytokine receptor signaling. See 147795 for background information on
Janus kinases.

CLONING

By screening a human placenta cDNA library with a probe encoding the
catalytic domain of rat Jak2, followed by EST database searching,
Saltzman et al. (1998) obtained a cDNA encoding a full-length JAK2
sequence. The JAK2 gene encodes a 1,132-amino acid protein that shares
95% sequence similarity to rat and pig Jak2. Northern blot analysis
detected expression of 3 transcripts of 7.6, 5.9 and 4.8 kb in all
tissues tested except heart and skeletal muscle. Highest expression was
found in spleen, peripheral blood leukocytes, and testis. In heart and
skeletal muscle, significant expression of 7.6-, 4.8-, and 3.9-kb
transcripts was found.

MAPPING

Pritchard et al. (1992) mapped the JAK2 gene to chromosome 9p24 by in
situ hybridization. Gough et al. (1995) mapped the homologous gene
(Jak2) to mouse chromosome 19 in a region of homology of synteny to
human 9.

GENE FUNCTION

Campbell et al. (1994) presented evidence that JAK2 is constitutively
associated with the prolactin receptor (PRLR; 176761) and that it is
activated and tyrosine phosphorylated upon PRL binding to the PRL
receptor. These results are consistent with JAK2 serving as an early,
perhaps initial, signaling molecule for prolactin.

Watling et al. (1993) isolated a cell line, selected for its inability
to express interferon (IFN)-gamma (147570)-inducible cell-surface
markers. The cell line was deficient in all aspects of IFN-gamma
response tested but responded normally to alpha and beta IFNs (see
147660). The mutant cells could be complemented by the expression of
JAK2. Unlike IFNs alpha and beta, IFN-gamma induced rapid tyrosine
phosphorylation of JAK2 in wildtype cells, and JAK2 immunoprecipitates
from these cells showed tyrosine kinase activity. These responses were
absent in the mutant cell line. JAK2 is, therefore, required for the
response to interferon-gamma but not to IFNs alpha and beta.

Saltzman et al. (1998) demonstrated that JAK2 phosphorylates STAT1
(600555), STAT2 (600556), STAT3 (102582), STAT4 (600558), and STAT5 (see
STAT5A, 601511, and STAT5B, 604260), but not STAT6 (601512).

STAT5 is activated in a broad spectrum of human hematologic
malignancies. Using a genetic approach, Schwaller et al. (2000)
addressed whether activation of STAT5 is necessary for the myelo- and
lymphoproliferative disease induced by the TEL (600618)/JAK2 fusion
gene. Whereas mice transplanted with bone marrow transduced with
retrovirus expressing TEL/JAK2 developed a rapidly fatal myelo- and
lymphoproliferative syndrome, reconstitution with bone marrow derived
from Stat5a/b-deficient mice expressing TEL/JAK2 did not induce disease.
Disease induction in the Stat5a/b-deficient background was rescued with
a bicistronic retrovirus encoding TEL/JAK2 and Stat5a. Furthermore,
myeloproliferative disease was induced by reconstitution with bone
marrow cells expressing a constitutively active mutant, Stat5a, or a
single Stat5a target, murine oncostatin M (OSM; 165095). These data
defined a critical role for STAT5A/B and OSM in the pathogenesis of
TEL/JAK2 disease.

In addition to its role as a kidney cytokine regulating hematopoiesis,
erythropoietin (133170) is also produced in the brain after oxidative or
nitrosative stress. The transcription factor HIF1 (603348) upregulates
erythropoietin following hypoxic stimuli. Digicaylioglu and Lipton
(2001) demonstrated that preconditioning with erythropoietin protects
neurons in models of ischemic and degenerative damage due to
excitotoxins and consequent generation of free radicals, including
nitric oxide. Activation of neuronal erythropoietin receptors (EPOR;
133171) prevents apoptosis induced by NMDA or nitric oxide by triggering
crosstalk between the signaling pathways JAK2 and NFKB (see 164011).
Digicaylioglu and Lipton (2001) demonstrated that erythropoietin
receptor-mediated activation of JAK2 leads to phosphorylation of the
inhibitor of NFKB (I-kappa-B-alpha; 164008), subsequent nuclear
translocation of the transcription factor NFKB, and NFKB-dependent
transcription of neuroprotective genes. Transfection of cerebrocortical
neurons with a dominant interfering form of JAK2 or an I-kappa-B-alpha
superrepressor blocks erythropoietin-mediated prevention of neuronal
apoptosis. Thus, neuronal erythropoietin receptors activate a
neuroprotective pathway that is distinct from previously well
characterized JAK and NFKB functions. Moreover, this erythropoietin
effect may underlie neuroprotection mediated by hypoxic-ischemic
preconditioning.

Huang et al. (2001) showed that JAK2, and more specifically just its
intact N-terminal domain, binds to EPOR in the endoplasmic reticulum and
promotes its cell surface expression. This interaction was specific, as
JAK1 had no effect. Residues 32 to 58 of the JAK2 JH7 domain were
required for EPOR surface expression. Alanine scanning mutagenesis of
the EPOR membrane proximal region revealed 2 modes of EPOR-JAK2
interaction. A continuous block of EPOR residues was required for
functional, ligand-independent binding to JAK2 and cell surface receptor
expression, whereas 4 specific residues were essential in switching on
prebound JAK2 after ligand binding. Thus, in addition to its kinase
activity required for cytokine receptor signaling, JAK is also an
essential subunit required for surface expression of cytokine receptors.

Dawson et al. (2009) showed that human JAK2 is present in the nucleus of
hematopoietic cells and directly phosphorylates tyr41 (Y41) on histone
H3 (see 602810). Heterochromatin protein 1-alpha (HP1-alpha, 604478),
but not HP1-beta (604511), specifically binds to this region of H3
through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2
prevents this binding. Inhibition of JAK2 activity in human leukemic
cells decreases both the expression of hematopoietic oncogene LMO2
(180385) and the phosphorylation of H3Y41 at its promoter, while
simultaneously increasing the binding of HP1-alpha at the same site.
Dawson et al. (2009) concluded that their results identified a
previously unrecognized nuclear role for JAK2 in the phosphorylation of
H3Y41 and revealed a direct mechanistic link between 2 genes, JAK2 and
LMO2, involved in normal hematopoiesis and leukemia.

Mullighan et al. (2009) reported a recurring interstitial deletion of
pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL
(613035) that juxtaposes the first, noncoding exon of P2RY8 (300525)
with the coding region of CRLF2 (300357). They identified the
P2RY8/CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of
individuals with ALL associated with Down syndrome. CRLF2 alteration was
associated with activating JAK mutations, and expression of human
P2RY8/CRLF2 together with mutated mouse Jak2 resulted in constitutive
JAK-STAT activation and cytokine-independent growth of Ba/F3 cells
overexpressing IL7 receptor-alpha (IL7R; 146661). Mullighan et al.
(2009) concluded that rearrangement of CRLF2 and JAK mutations together
contribute to leukemogenesis in B-progenitor ALL.

MOLECULAR GENETICS

Polycythemia vera (263300), thrombocythemia (THCYT3; 614521), and
idiopathic myelofibrosis (254450) are clonal myeloproliferative
disorders arising from a multipotent progenitor. The loss of
heterozygosity (LOH) on chromosome 9p in myeloproliferative disorders
suggested that 9p harbors a mutation that contributes to the cause of
clonal expansion of hematopoietic cells in these diseases. Baxter et al.
(2005) and Kralovics et al. (2005) found that a high proportion of
patients with these myeloproliferative disorders carried a dominant
somatic gain-of-function val617-to-phe mutation in the JAK2 gene (V617F;
147796.0001).

James et al. (2005) identified a somatic V617F mutation in 40 of 45
patients with polycythemia vera. They found that the mutation leads to
constitutive tyrosine phosphorylation activity that promotes cytokine
hypersensitivity and induces erythrocytosis in a mouse model.

Using granulocyte-based mutation screening in 220 patients with either
polycythemia vera or myelofibrosis with myeloid metaplasia, Tefferi et
al. (2005) identified 21 patients who were homozygous for the V617F
mutation of JAK2; 13 had polycythemia vera and 8 had myelofibrosis with
myeloid metaplasia. Kralovics et al. (2005) proposed a 2-step model for
the role of JAK2 (V617F) in the clonal evolution of myeloproliferative
disorders. The first step consists, in their view, of a G-to-T mutation
in 1 allele of the JAK2 gene that is acquired as a somatic mutation in a
hematopoietic progenitor cell or stem cell. This cell gives rise to a
clone that is heterozygous for V617F and expands to replace
hematopoietic cells without the JAK2 mutation. The second step consists
of a mitotic recombination in 1 of the progenitor cells or stem cells
heterozygous for the JAK2 mutation that generates uniparental disomy and
homozygosity for JAK2 (V617F) in 1 of the 2 daughter cells. This
daughter cell gives rise to a clone that is homozygous for V617F and
expands to replace heterozygous hematopoietic cells.

Lee et al. (2006) identified heterozygosity for mutations in the JAK2
gene (V617F and K607N, 147796.0002) in bone marrow aspirates from 3
(2.7%) of 113 unrelated patients with acute myelogenous leukemia (AML;
601626). JAK2 mutations were not found in 94 ductal breast carcinomas,
104 colorectal carcinomas, or 217 nonsmall cell lung cancers.

Scott et al. (2007) searched for new mutations in members of the JAK and
signal transducer and activator of transcription (STAT; see 600555) gene
families in patients with V617F-negative polycythemia vera or idiopathic
erythrocytosis (see 133100). They identified 4 somatic gain-of-function
mutations affecting exon 12 of JAK2 in 10 of the V617F-negative
patients. Those with a JAK2 exon 12 mutation presented with an isolated
erythrocytosis and distinctive bone marrow morphology, and several also
had reduced serum erythropoietin levels. Erythroid colonies could be
grown from their blood samples in the absence of exogenous
erythropoietin. All such erythroid colonies were heterozygous for the
mutation, whereas colonies homozygous for the mutation occur in most
patients with V617F-positive polycythemia vera. BaF3 cells expressing
the murine erythropoietin receptor and also carrying exon 12 mutations
could proliferate without added interleukin-3 (147740). They also
exhibited increased phosphorylation of JAK2 and extracellular
signal-regulated kinase 1 (ERK1; 176872) and 2 (ERK2; 176948), as
compared with cells transduced by wildtype JAK2 or V617F JAK2. Three of
the exon 12 mutations included a substitution of leucine for lysine at
position 539 of JAK2 (147796.0003). This mutation resulted in a
myeloproliferative phenotype, including erythrocytosis, in a murine
model of retroviral bone marrow transplantation.

Bercovich et al. (2008) identified somatic JAK2 mutations in 16 (18%) of
88 patients with Down syndrome (190685)-associated acute lymphoblastic
leukemia (ALL). Only 1 of 109 patients with non-Down syndrome-associated
leukemia had the mutation, but this child was also found to have an
isochromosome 21q. All the JAK2-associated leukemias were of the B-cell
precursor type. Children with a JAK2 mutation were younger (mean age,
4.5 years) compared to patients without JAK2 mutations (8.6 years) at
diagnosis. Five mutant JAK2 alleles were identified, each affecting a
highly conserved residue: arg683 (i.e., R683G, R683S, R683K). In vitro
functional expression studies in mouse hematopoietic progenitor cells
showed that the mutations caused constitutive Jak/Stat activation and
cytokine-independent growth, consistent with a gain of function. This
growth was sensitive to pharmacologic inhibition with a JAK inhibitor.
Modeling studies showed that arg683 is located in an exposed conserved
region of the JAK2 pseudokinase domain in a region different from that
implicated in myeloproliferative disorders. Bercovich et al. (2008)
concluded that there is a specific association between constitutional
trisomy 21 and arg683 JAK2 mutations that predisposes to the development
of B-cell ALL in patients with Down syndrome.

- Germline JAK2 Mutation

In a case-control study of unexplained pregnancy loss (see 614389),
Mercier et al. (2007) found association between the JAK2 V617F mutation
and the risk of fetal or embryonic loss. However, Dahabreh et al. (2008)
found no evidence for increased prevalence of the JAK2 V617F mutation in
women with a history of recurrent miscarriage.

By genomewide analysis of 181 individuals with polycythemia vera or
essential thrombocytosis, Kilpivaara et al. (2009) identified a C-G
transversion in intron 12 (dbSNP rs10974944) that predisposed to the
development of V617F-positive myeloproliferative neoplasms. The minor G
allele of this SNP was significantly more common among 324 individuals
with polycythemia vera, essential thrombocythemia, or primary
myelofibrosis, compared to controls (odds ratio of 3.1; p = 4.1 x
10(-20)). The V617F mutation was preferentially acquired in cis with the
predisposition allele. These data suggested that germline variations are
an important contributor to myeloproliferative phenotype and
predisposition associated with somatic mutations.

Jones et al. (2009) found that 109 (77%) of 142 alleles harboring the
JAK2 V617F mutation from patients with a myeloproliferative neoplasm had
the JAK2 46/1 haplotype, which was tagged by dbSNP rs12343867 in intron
14 and dbSNP rs12340895, compared to only 9 (12%) of the 74 residual
wildtype alleles (p = 1.4 x 10(-20)). The results indicated that
homozygosity for V617F was not random, but rather occurred
preferentially when this mutation was present on the specific JAK2
haplotype. Additional analysis in 177 heterozygous V617F carriers found
that V617F occurred more frequently on the 46/1 haplotype (135 of 354
alleles) compared to 188 controls (92 of 376 alleles; p = 0.0001) and
1,500 controls (p = 3.3 x 10(-8)). Sequencing of the products in 66
informative cases showed that 49 (74%) V617F alleles arose on the 46/1
allele, whereas only 17 (26%) wildtype alleles were on 46/1 (p = 2.1 x
10(-8)). V617F-associated disease was strongly associated with haplotype
46/1 in all 3 disease entities compared to healthy controls:
polycythemia vera (p = 2.9 x 10(-16)), essential thrombocythemia (p =
8.2 x 10(-9)), and myelofibrosis (p = 8.0 x 10(-5)). Jones et al. (2009)
concluded that the 46/1 haplotype predisposes to the development of
V617F-associated myeloproliferative neoplasms, with an overall odds
ratio of 3.7.

Olcaydu et al. (2009) also found that a JAK2 haplotype including dbSNP
rs12343867 preferentially acquired the V617F mutation and conferred
susceptibility to myeloproliferative disorders. Ninety-three (85%) of
109 individuals with myeloproliferative disorders who were heterozygous
for dbSNP rs12343867 carried the V617F mutation on the C allele (p = 7.8
x 10(-15)). Olcaydu et al. (2009) suggested that a certain combination
of SNPs may render haplotypes differentially susceptible to somatic
mutagenesis.

In affected members of a family with autosomal dominant
thrombocythemia-3 (THCYT3; 614521), Mead et al. (2012) identified a
germline heterozygous G-to-A transition in the JAK2 gene, resulting in a
val617-to-ile (V617I) substitution. The proband presented at age 53
years with an ischemic cerebrovascular event associated with
long-standing thrombocytosis (700 x 10(9) to 970 x 10(9)). There were 5
additional family members with thrombocytosis, including 1 with a
myocardial infarction at age 46 and another with a myocardial infarction
at age 65 and an ischemic cerebrovascular event at age 72. Bone marrow
biopsy showed megakaryocyte hyperplasia without fibrosis. In addition,
none of the patients had splenomegaly or evidence of leukemic
transformation. Examination of peripheral blood cells showed normal
baseline STAT3 (102582) activity and lack of cytokine-independent colony
formation. However, after stimulation with granulocyte
colony-stimulating factor (GCSF; 138970), V617I-containing CD33+ myeloid
and CD34+ stem cells showed a marked increase in STAT3 levels,
particularly in response to low levels of GCSF, suggesting that the
mutation causes limited constitutive activation with a reduced threshold
for cytokine-induced activation.

CYTOGENETICS

- ETV6/JAK2 Fusion Gene

Peeters et al. (1997) identified a t(9;12)(p24;p13) translocation in a
patient with early pre-B acute lymphoid leukemia and a
t(9;15;12)(p24;q15;p13) translocation in a patient with atypical chronic
myelogenous leukemia (CML; 608232) in transformation. Both changes
involved the ETV6 gene (600618) at 12p13 and the JAK2 gene at 9p24. In
each case different fusion mRNAs were found, with only 1 resulting in a
chimeric protein consisting of the oligomerization domain of ETV6 and
the protein tyrosine kinase domain of JAK2.

Lacronique et al. (1997) observed a t(9;12)(p24;p13) translocation in
leukemic cells from a 4-year-old boy with T-cell ALL. The 3-prime
portion of the JAK2 gene was fused to the 5-prime portion of the ETV6
gene, resulting in a protein containing the catalytic domain of JAK2 and
the oligomerization domain of ETV6. The resultant protein had
constitutive tyrosine kinase activity and conferred cytokine-independent
proliferation to a murine cell line.

ANIMAL MODEL

To assess the role of JAK2, Parganas et al. (1998) derived
Jak2-deficient mice by targeted disruption of the mouse gene in
embryonic stem cells. The mutation caused an embryonic lethality due to
the absence of definitive erythropoiesis. Fetal liver myeloid
progenitors, although present based on the expression of
lineage-specific markers, failed to respond to erythropoietin,
thrombopoietin (600044), interleukin-3 (147740), or
granulocyte/macrophage colony-stimulating factor (138960). In contrast,
the response to granulocyte-specific colony-stimulating factor was
unaffected. Jak2-deficient fibroblasts failed to respond to IFN-gamma,
although the responses to IFN-alpha/beta and interleukin-6 (147620) were
unaffected. Reconstitution experiments demonstrated that Jak2 was not
required for the generation of lymphoid progenitors, their
amplification, or their functional differentiation. Parganas et al.
(1998) concluded that Jak2 plays a critical, nonredundant role in the
function of a specific group of cytokine receptors.

Neubauer et al. (1998) also performed a targeted inactivation of Jak2 in
mice. Jak2 -/- embryos were anemic and died around day 12.5 postcoitum.
Primitive erythrocytes were found, but definitive erythropoiesis was
absent. Compared to erythropoietin receptor-deficient mice, the
phenotype of Jak2 deficiency was more severe. Fetal liver BFU-E and
CFU-E colonies were completely absent. However, multilineage
hematopoietic stem cells (CD34-low, c-kit-pos) were found, and B
lymphopoiesis appeared intact. In contrast to IFN-alpha stimulation,
Jak2 -/- cells did not respond to IFN-gamma. Jak2 -/- embryonic stem
cells were competent for LIF signaling. These data also demonstrated
that Jak2 has pivotal functions for signal transduction of a set of
cytokine receptors required in definitive erythropoiesis.

*FIELD* AV
.0001
POLYCYTHEMIA VERA, SOMATIC
THROMBOCYTHEMIA 3, SOMATIC, INCLUDED;;
MYELOFIBROSIS, SOMATIC, INCLUDED;;
ERYTHROCYTOSIS, SOMATIC, INCLUDED;;
LEUKEMIA, ACUTE MYELOGENOUS, SOMATIC, INCLUDED;;
BUDD-CHIARI SYNDROME, SUSCEPTIBILITY TO, SOMATIC, INCLUDED
JAK2, VAL617PHE

---Polycythemia Vera, Thrombocythemia, Myelofibrosis, or Erythrocytosis

In 71 (97%) of 73 patients with polycythemia vera (PV; 263300), 29 (57%)
of 51 with essential thrombocythemia (THCYT3; 614521), and 8 (50%) of 16
with idiopathic myelofibrosis (254450), Baxter et al. (2005) identified
a somatic G-to-T transversion in the JAK2 gene, resulting in a
val617-to-phe (V617F) substitution in the negative regulatory JH2
domain. The mutation was predicted to dysregulate kinase activity. It
was heterozygous in most patients, homozygous in a subset as the result
of mitotic recombination, and arose in a multipotent progenitor capable
of giving rise to erythroid and myeloid cells.

In all 51 patients with loss-of-heterozygosity (LOH) of chromosome 9p,
Kralovics et al. (2005) identified a somatic V617F mutation. Of 193
patients without 9p LOH, 66 were heterozygous for V617F and 127 did not
have the mutation. The frequency of V617F was 65% (83 of 128) among
patients with polycythemia vera, 57% (13 of 23) among patients with
idiopathic myelofibrosis, and 23% (21 of 93) among patients with
essential thrombocythemia.

James et al. (2005) identified a somatic V617F mutation in 40 of 45
patients with polycythemia vera. They found that the mutation leads to
constitutive tyrosine phosphorylation activity that promotes cytokine
hypersensitivity and induces erythrocytosis in a mouse model.

Jamieson et al. (2006) identified the V617F mutation in peripheral blood
and bone marrow cells in 14 of 16 PV patients. In all PV peripheral
blood samples analyzed, there were increased numbers of hematopoietic
stem cells compared to controls. The V617F mutation was detected in
hematopoietic stem cells of all 6 PV samples examined further, and those
stem cells showed skewed differentiation towards the erythroid lineage.
However, the mutation was also identified in most myeloid precursor
cells examined, indicating that the mutation was clonally transmitted to
all stem cell progeny. Aberrant erythroid potential of PV stem cells was
potently inhibited by the JAK2 inhibitor AG490.

An acquired V617F mutation in JAK2 occurs in most patients with
polycythemia vera, but is seen in only half those with essential
thrombocythemia and idiopathic myelofibrosis. Campbell et al. (2005)
attempted to determine whether essential thrombocythemia patients with
the mutation are biologically distinct from those without, and why the
same mutation is associated with different disease phenotypes. The
mutation-positive patients had lower serum erythropoietin and ferritin
concentrations than did mutation-negative patients. Mutation-negative
patients did, nonetheless, show many clinical and laboratory features
characteristic of a myeloproliferative disorder. These V617F-positive
individuals were more sensitive to therapy with hydroxyurea, but not
anagrelide, than those without the JAK2 mutation. Thus, Campbell et al.
(2005) concluded that V617F-positive essential thrombocythemia and
polycythemia vera form a biologic continuum, with the degree of
erythrocytosis determined by physiologic or genetic modifiers.

---Acute Myelogeneous Leukemia

Lee et al. (2006) identified heterozygosity for the V617F mutation in
bone marrow aspirates from 2 of 113 patients with acute myelogenous
leukemia (AML; 601626). Neither patient had a history of previous
hematologic disorders and or evidence of erythroid lineage proliferation
on bone marrow biopsy.

---Susceptibility to Pregnancy Loss

Mercier et al. (2007) screened for the JAK2 V617F mutation in 3,496
pairs of women enrolled in a matched case-control study of unexplained
pregnancy loss (see RPRGL1, 614389) and found that the mutation was
significantly associated with the risk of fetal loss (OR, 4.63; p =
0.002) and embryonic loss (OR, 7.20; p = 0.009). The mutation was more
frequent in women with embryonic loss than in those with fetal loss (p
less than 0.001); clinical examination and complete blood count were
normal in all women with the mutation. The increased risks were
independent of those associated with the 1691A mutation in the factor V
Leiden gene (612309.0001) and the 20210A mutation in the prothrombin
gene (176930.0009).

Dahabreh et al. (2008) screened 389 women with a history of at least 3
consecutive early or 1 late pregnancy loss but did not find the JAK2
V617F mutation in any case; the authors concluded that latent maternal
JAK2 V617F-positive myoproliferative neoplasm is an unlikely cause of
miscarriage.

---Budd-Chiari Syndrome

Chung et al. (2006) described Budd-Chiari syndrome (600880) in a
46-year-old woman who was well until the onset of increasing abdominal
distention over a period of several days. She was found to have a
combination of the V617F mutation and the factor V Leiden mutation
(612309.0001). This JAK2 mutation was found by Patel et al. (2006) in a
high proportion of patients with the Budd-Chiari syndrome, providing
evidence that these patients have a latent myeloproliferative disorder.

Sozer et al. (2009) identified somatic homozygous V617F mutations in
liver venule endothelial and hematopoietic cells from 2 unrelated PV
patients who developed Budd-Chiari syndrome. However, analysis of
endothelial cells from a third PV patient with Budd-Chiari syndrome and
in 2 patients with hepatoportal sclerosis without PV showed only
wildtype JAK2. Endothelial and hematopoietic cells are believed to come
from a common progenitor called the hemangioblast. Sozer et al. (2009)
concluded that finding V617F-positive endothelial cells and
hematopoietic cells from patients with PV who developed Budd-Chiari
syndrome indicates that endothelial cells are involved by the PV
malignant process, and suggested that the disease might originate from a
common cell of origin in some patients.

.0002
LEUKEMIA, ACUTE MYELOGENOUS, SOMATIC
JAK2, LYS607ASN

In bone marrow aspirate from 1 of 113 patients with acute myelogenous
leukemia (AML; 601626), Lee et al. (2006) identified a heterozygous
1821G-C transversion in the twelfth coding exon (exon 14) of the JAK2
gene, resulting in a lys607-to-asn (K607N) substitution in a conserved
residue in the pseudokinase domain.

.0003
ERYTHROCYTOSIS, JAK2-RELATED, SOMATIC
JAK2, LYS539LEU

Among 10 patients with a diagnosis of polycythemia vera or idiopathic
erythrocytosis (see 133100) who did not carry the V617F mutation in JAK2
(147796.0001), Scott et al. (2007) found 3 alleles carrying a somatic
lys539-to-leu substitution (K539L) in exon 12 of the JAK2 gene. Those
with this and 3 other JAK2 exon 12 mutations presented with an isolated
erythrocytosis and distinctive bone marrow morphology, and several also
had reduced serum erythropoietin levels. Erythroid colonies could be
grown from their blood samples in the absence of exogenous
erythropoietin. All such erythroid colonies were heterozygous for the
mutation, whereas colonies homozygous for the mutation occurred in most
patients with V617F-positive polycythemia vera. The K539L mutation
resulted in a myeloproliferative phenotype, including erythrocytosis, in
a murine model of retroviral bone marrow transplantation.

.0004
THROMBOCYTHEMIA 3
JAK2, VAL617ILE

In affected members of a family with autosomal dominant
thrombocythemia-3 (THCYT3; 614521), Mead et al. (2012) identified a
germline heterozygous G-to-A transition in the JAK2 gene, resulting in a
val617-to-ile (V617I) substitution. The proband presented at age 53
years with an ischemic cerebrovascular event associated with
long-standing thrombocytosis (700 x 10(9) to 970 x 10(9)). There were 5
additional family members with thrombocytosis, including 1 with a
myocardial infarction at age 46 and another with a myocardial infarction
at age 65 and an ischemic cerebrovascular event at age 72. Bone marrow
biopsy showed megakaryocyte hyperplasia without fibrosis. In addition,
none of the patients had splenomegaly or evidence of leukemic
transformation. Examination of peripheral blood cells showed normal
baseline STAT3 (102582) activity and lack of cytokine-independent colony
formation. However, after stimulation with (GCSF; 138970),
V617I-containing CD33+ myeloid and CD34+ stem cells showed a marked
increase in STAT3 levels, particularly in response to low levels of
GCSF, suggesting that the mutation causes limited constitutive
activation with a reduced threshold for cytokine-induced activation.

*FIELD* RF
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Cross, N. C. P.: JAK2 haplotype is a major risk factor for the development
of myeloproliferative neoplasms. Nature Genet. 41: 446-449, 2009.

14. Kilpivaara, O.; Mukherjee, S.; Schram, A. M.; Wadleigh, M.; Mullally,
A.; Ebert, B. L.; Bass, A.; Marubayashi, S.; Heguy, A.; Garcia-Manero,
G.; Kantarjian, H.; Offit, K.; Stone, R. M.; Gilliland, D. G.; Klein,
R. J.; Levine, R. L.: A germline JAK2 SNP is associated with predisposition
to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nature
Genet. 41: 455-459, 2009.

15. Kralovics, R.; Cazzola, M.; Skoda, R. C.: Reply to Tefferi et
al. (Letter) New Eng. J. Med. 353: 1417 only, 2005.

16. Kralovics, R.; Passamonti, F.; Buser, A. S.; Teo, S.-S.; Tiedt,
R.; Passweg, J. R.; Tichelli, A.; Cazzola, M.; Skoda, R. C.: A gain-of-function
mutation of JAK2 in myeloproliferative disorders. New Eng. J. Med. 352:
1779-1790, 2005.

17. Lacronique, V.; Boureux, A.; Della Valle, V.; Poirel, H.; Quang,
C. T.; Mauchauffe, M.; Berthou, C.; Lessard, M.; Berger, R.; Ghysdael,
J.; Bernard, O. A.: A TEL-JAK2 fusion protein with constitutive kinase
activity in human leukemia. Science 278: 1309-1312, 1997.

18. Lee, J. W.; Kim, Y. G.; Soung, Y. H.; Han, K. J.; Kim, S. Y.;
Rhim, H. S.; Min, W. S.; Nam, S. W.; Park, W. S.; Lee, J. Y.; Yoo,
N. J.; Lee, S. H.: The JAK2 V617F mutation in de novo acute myelogenous
leukemias. Oncogene 25: 1434-1436, 2006.

19. Mead, A. J.; Rugless, M. J.; Jacobsen, S. E. W.: Schuh, A.: Germline
JAK2 mutation in a family with hereditary thrombocytosis. (Letter) New
Eng. J. Med. 366: 967-969, 2012.

20. Mercier, E.; Lissalde-Lavigne, G.; Gris, J.-C.: JAK2 V617F mutation
in unexplained loss of first pregnancy. (Letter) New Eng. J. Med. 357:
1984-1985, 2007.

21. Mullighan, C. G.; Collins-Underwood, J. R.; Phillips, L. A. A.;
Loudin, M. G.; Liu, W.; Zhang, J.; Ma, J.; Coustan-Smith, E.; Harvey,
R. C.; Willman, C. L.; Mikhail, F. M.; Meyer, J.; and 12 others
: Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated
acute lymphoblastic leukemia. Nature Genet. 41: 1243-1246, 2009.

22. Neubauer, H.; Cumano, A.; Muller, M.; Wu, H.; Huffstadt, U.; Pfeffer,
K.: Jak2 deficiency defines an essential developmental checkpoint
in definitive hematopoiesis. Cell 93: 397-409, 1998.

23. Olcaydu, D.; Harutyunyan, A.; Jager, R.; Berg, T.; Gisslinger,
B.; Pabinger, I.; Gisslinger, H.; Kralovics, R.: A common JAK2 haplotype
confers susceptibility to myeloproliferative neoplasms. Nature Genet. 41:
450-454, 2009.

24. Parganas, E.; Wang, D.; Stravopodis, D.; Topham, D. J.; Marine,
J.-C.; Teglund, S.; Vanin, E. F.; Bodner, S.; Colamonici, O. R.; van
Deursen, J. M.; Grosveld, G.; Ihle, J. N.: Jak2 is essential for
signaling through a variety of cytokine receptors. Cell 93: 385-395,
1998.

25. Patel, R. K.; Lea, N. C.; Heneghan, M. A.; Westwood, N. B.; Milojkovic,
D.; Thanigaikumar, M.; Yallop, D.; Arya, R.; Pagliuca, A.; Gaken,
J.; Wendon, J.; Heaton, N. D.; Mufti, G. J.: Prevalence of the activating
JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastroenterology 130:
2031-2038, 2006.

26. Peeters, P.; Raynaud, S. D.; Cools, J.; Wlodarska, I.; Grosgeorge,
J.; Philip, P.; Monpoux, F.; Van Rompaey, L.; Baens, M.; Van den Berghe,
H.; Marynen, P.: Fusion of TEL, the ETS-variant gene 6 (ETV6), to
the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid
and t(9;15;12) in a myeloid leukemia. Blood 90: 2535-2540, 1997.

27. Pritchard, M. A.; Baker, E.; Callen, D. F.; Sutherland, G. R.;
Wilks, A. F.: Two members of the JAK family of protein tyrosine kinases
map to chromosomes 1p31.3 and 9p24. Mammalian Genome 3: 36-38, 1992.

28. Saltzman, A.; Stone, M.; Franks, C.; Searfoss, G.; Munro, R.;
Jaye, M.; Ivashchenko, Y.: Cloning and characterization of human
Jak-2 kinase: high mRNA expression in immune cells and muscle tissue. Biochem.
Biophys. Res. Commun. 246: 627-633, 1998.

29. Schwaller, J.; Parganas, E.; Wang, D.; Cain, D.; Aster, J. C.;
Williams, I. R.; Lee, C.-K.; Gerthner, R.; Kitamura, T.; Frantsve,
J.; Anastasiadou, E.; Loh, M. L.; Levy, D. E.; Ihle, J. N.; Gilliland,
D. G.: Stat5 is essential for the myelo- and lymphoproliferative
disease induced by TEL/JAK2. Molec. Cell 6: 693-704, 2000.

30. Scott, L. M.; Tong, W.; Levine, R. L.; Scott, M. A.; Beer, P.
A.; Stratton, M. R.; Futreal, P. A.; Erber, W. N.; McMullin, M. F.;
Harrison, C. N.; Warren, A. J.; Gilliland, D. G.; Lodish, H. F.; Green,
A. R.: JAK2 exon 12 mutations in polycythemia vera and idiopathic
erythrocytosis. New Eng. J. Med. 356: 459-468, 2007. Note: Erratum:
New Eng. J. Med. 357: 1457 only, 2007.

31. Sozer, S.; Fiel, M. I.; Schiano, T.; Xu, M.; Mascarenhas, J.;
Hoffman, R.: The presence of JAK2V617F mutation in the liver endothelial
cells of patients with Budd-Chiari syndrome. Blood 113: 5246-5249,
2009.

32. Tefferi, A.; Lasho, T. L.; Gilliland, G.: JAK2 mutations in myeloproliferative
disorders. (Letter) New Eng. J. Med. 353: 1416-1417, 2005.

33. Watling, D.; Guschin, D.; Muller, M.; Silvennoinen, O.; Witthuhn,
B. A.; Quelle, F. W.; Rogers, N. C.; Schindler, C.; Stark, G. R.;
Ihle, J. N.; Kerr, I. M.: Complementation by the protein tyrosine
kinase JAK2 of a mutant cell line defective in the interferon-gamma
signal transduction pathway. Nature 366: 166-170, 1993.

*FIELD* CN
Cassandra L. Kniffin - updated: 3/8/2012
Ada Hamosh - updated: 2/16/2010
Cassandra L. Kniffin - updated: 12/29/2009
Cassandra L. Kniffin - updated: 11/13/2009
Ada Hamosh - updated: 11/5/2009
Marla J. F. O'Neill - updated: 9/10/2009
Cassandra L. Kniffin - updated: 6/8/2009
Cassandra L. Kniffin - updated: 12/16/2008
Marla J. F. O'Neill - updated: 12/4/2007
Victor A. McKusick - updated: 2/26/2007
Cassandra L. Kniffin - updated: 6/20/2006
Victor A. McKusick - updated: 6/8/2006
Cassandra L. Kniffin - updated: 5/24/2006
Victor A. McKusick - updated: 10/26/2005
Ada Hamosh - updated: 5/25/2005
Victor A. McKusick - updated: 5/10/2005
Stylianos E. Antonarakis - updated: 1/4/2002
Anne M. Stumpf - updated: 8/17/2001
Ada Hamosh - updated: 8/15/2001
Stylianos E. Antonarakis - updated: 10/11/2000
Stylianos E. Antonarakis - updated: 6/1/1998

*FIELD* CD
Victor A. McKusick: 9/4/1992

*FIELD* ED
alopez: 01/28/2014
mgross: 2/5/2013
carol: 7/20/2012
terry: 3/9/2012
carol: 3/9/2012
ckniffin: 3/8/2012
alopez: 12/13/2011
carol: 7/12/2011
wwang: 10/26/2010
ckniffin: 10/25/2010
ckniffin: 9/3/2010
alopez: 3/2/2010
terry: 2/16/2010
wwang: 1/13/2010
ckniffin: 12/29/2009
wwang: 12/1/2009
ckniffin: 11/13/2009
alopez: 11/9/2009
terry: 11/5/2009
wwang: 9/22/2009
terry: 9/10/2009
wwang: 6/17/2009
ckniffin: 6/8/2009
wwang: 12/16/2008
carol: 10/8/2008
terry: 6/6/2008
ckniffin: 3/27/2008
carol: 12/6/2007
carol: 12/5/2007
terry: 12/4/2007
carol: 4/20/2007
carol: 4/11/2007
alopez: 3/21/2007
terry: 2/26/2007
wwang: 6/23/2006
ckniffin: 6/20/2006
alopez: 6/9/2006
terry: 6/8/2006
wwang: 6/5/2006
ckniffin: 5/24/2006
carol: 11/14/2005
alopez: 10/27/2005
terry: 10/26/2005
terry: 5/25/2005
tkritzer: 5/16/2005
terry: 5/10/2005
mgross: 1/4/2002
carol: 8/17/2001
alopez: 8/17/2001
terry: 8/15/2001
mgross: 10/11/2000
carol: 6/2/1998
terry: 6/1/1998
mark: 5/11/1995
jason: 7/12/1994
carol: 5/28/1993
carol: 9/4/1992

MIM 254450
*RECORD*
*FIELD* NO
254450
*FIELD* TI
#254450 MYELOFIBROSIS
MYELOFIBROSIS WITH MYELOID METAPLASIA, INCLUDED; MMM, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that many
cases of myelofibrosis are associated with a somatic mutation in the
JAK2 gene (147796) on chromosome 9p, somatic mutation in the MPL gene
(159530) on 1p34, or somatic mutation in the CALR gene (109091) on
chromosome 19p13.

Somatic mutations in the TET2 gene (612839), the ASXL1 gene (612990),
the SH2B3 gene (605093), the SF3B1 gene (605590), and the NFE2 gene
(601490) have also been found in cases of myelofibrosis.

CLINICAL FEATURES

Sieff and Malleson (1980) described a brother and sister who developed
fulminant fatal myeloproliferative disease at 7 and 8 weeks of age. The
bone marrow showed reduced hemopoiesis with generalized fibrosis.
Although clinically resembling familial hemophagocytic reticulosis, the
disorder did not show the characteristic hemophagocytosis as a prominent
feature. The parents were not related.

Bonduel et al. (1998) reported 2 sisters, born of nonconsanguineous
parents, with idiopathic myelofibrosis and multiple hemangiomas. The
older sister presented at 4 years of age with pallor, weakness, and
purpura; the younger sister was hospitalized at 7 months of age because
of fever and splenomegaly. Multiple small hemangiomas were pictured on
the neck and back of the older sister.

MOLECULAR GENETICS

Baxter et al. (2005) and Kralovics et al. (2005) found that 50% (8 of
16) and 57% (13 of 23) of patients with idiopathic myelofibrosis,
respectively, carried a somatic mutation in the JAK2 gene (V617F;
147796.0001).

Pikman et al. (2006) identified a somatic mutation in the MPL gene
(W515L; 159530.0011) in 4 (9%) of 45 patients with myelofibrosis with
myeloid metaplasia (MMM). Two of the patients also had leukocytosis and
thrombocytosis at the time of disease presentation. Functional
expression studies showed that this was an activating mutation
conferring cytokine-independent growth and hypersensitivity to
thrombopoietin (THPO; 600044) in cell culture. Pardanani et al. (2006)
identified somatic mutations in the MPL gene (W515L and W515K;
159530.0011) in 9 patients with myelofibrosis with myeloid metaplasia.
Some of these patients were also heterozygous for the JAK2 V617F
mutation.

Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow
cells from 320 patients with myeloid cancers and identified TET2 defects
in 4 patients with primary myelofibrosis, 3 of whom also displayed the
JAK2 V617F mutation.

Jutzi et al. (2013) identified 7 different somatic insertion or deletion
mutations in the NFE2 gene (601490) in 8 patients with
myeloproliferative disorders, including 3 with polycythemia vera (PV;
263300) and 5 with myelofibrosis, either primary or secondary. In vitro
studies showed that the mutant truncated NFE2 proteins were unable to
bind DNA and had lost reporter gene activity. However, coexpression of
mutant NFE2 constructs with wildtype NFE2 resulted in significantly
enhanced transcriptional activity. Analysis of patient cells showed low
levels of the mutant truncated protein, but increased levels of the
wildtype NFE2 protein compared to control cells, likely due to both
increased mRNA and increased stability of the wildtype protein. All 7
patients tested also carried a JAK2 V617F mutation (147796.0001).
Hematopoietic cell colonies grown from 3 patients showed that the NFE2
mutation was acquired subsequent to the JAK2 mutation, and further
cellular studies indicated that an NFE2 mutation conferred a
proliferative advantage of cells compared to cells carrying only the
JAK2 mutation. Cells carrying mutant NFE2 displayed an increase in the
proportion of cells in the S phase, consistent with enhanced cell
division and proliferation, and this was associated with higher levels
of cell cycle regulators. These findings were replicated in mice
carrying NFE2 mutations, who developed thrombocytosis, erythrocytosis,
and neutrophilia.

ANIMAL MODEL

Kaufmann et al. (2012) found that mice with overexpression of the Nfe2
gene in hematopoietic cells developed features of myeloproliferative
disorders, including thrombocytosis, leukocytosis, Epo-independent
colony formation, characteristic bone marrow histology, expansion of
stem and progenitor compartments, and spontaneous transformation to
acute myeloid leukemia. This phenotype was transplantable to secondary
recipient mice. Cells from Nfe2 transgenic mice showed hypoacetylation
of histone H3 (602810). Treatment of mice with a histone deacetylase
inhibitor (HDAC-I) restored physiologic levels of histone H3
acetylation, decreased Nfe2 expression, and normalized platelet numbers.
Similarly, patients with myeloproliferative disorders treated with an
HDAC-I showed a decrease in NFE2 expression. These data established a
role for aberrant NFE2 expression in the pathophysiology of
myeloproliferative disorders.

*FIELD* RF
1. Baxter, E. J.; Scott, L. M.; Campbell, P. J.; East, C.; Fourouclas,
N.; Swanton, S.; Vassiliou, G. S.; Bench, A. J.; Boyd, E. M.; Curtin,
N.; Scott, M. A.; Erber, W. N.; Cancer Genome Project; Green, A.
R.: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative
disorders. Lancet 365: 1054-1061, 2005. Note: Erratum: Lancet 366:
122 only, 2005.

2. Bonduel, M.; Sciuccati, G.; Torres, A. F.; Pierini, A.; Galla,
G.: Familial idiopathic myelofibrosis and multiple hemangiomas. Am.
J. Hemat. 59: 175-177, 1998.

3. Delhommeau, F.; Dupont, S.; Della Valle, V.; James, C.; Trannoy,
S.; Masse, A.; Kosmider, O.; Le Couedic, J.-P.; Robert, F.; Alberdi,
A.; Lecluse, Y.; Plo, I.; and 11 others: Mutation in TET2 in myeloid
cancers. New Eng. J. Med. 360: 2289-2301, 2009.

4. Jutzi, J. S.; Bogeska, R.; Nikoloski, G.; Schmid, C. A.; Seeger,
T. S.; Stegelmann, F.; Schwemmers, S.; Grunder, A.; Peeken, J. C.;
Gothwal, M.; Wehrle, J.; Aumann, K.; Hamdi, K.; Dierks, C.; Wang,
W.; Dohner, K.; Jansen, J. H.; Pahl, H. L.: MPN patients harbor recurrent
truncating mutations in transcription factor NF-E2. J. Exp. Med. 210:
1003-1019, 2013.

5. Kaufmann, K. B.; Grunder, A.; Hadlich, T.; Wehrle, J.; Gothwal,
M.; Bogeska, R.; Seeger, T. S.; Kayser, S.; Pham, K.-B.; Jutzi, J.
S.; Ganzenmuller, L.; Steinemann, D.; and 11 others: A novel murine
model of myeloproliferative disorders generated by overexpression
of the transcription factor NF-E2. J. Exp. Med. 209: 35-50, 2012.

6. Kralovics, R.; Passamonti, F.; Buser, A. S.; Teo, S.-S.; Tiedt,
R.; Passweg, J. R.; Tichelli, A.; Cazzola, M.; Skoda, R. C.: A gain-of-function
mutation of JAK2 in myeloproliferative disorders. New Eng. J. Med. 352:
1779-1790, 2005.

7. Pardanani, A. D.; Levine, R. L.; Lasho, T.; Pikman, Y.; Mesa, R.
A.; Wadleigh, M.; Steensma, D. P.; Elliott, M. A.; Wolanskyj, A. P.;
Hogan, W. J.; McClure, R. F.; Litzow, M. R.; Gilliland, D. G.; Tefferi,
A.: MPL515 mutations in myeloproliferative and other myeloid disorders:
a study of 1182 patients. Blood 108: 3472-3476, 2006.

8. Pikman, Y.; Lee, B. H.; Mercher, T.; McDowell, E.; Ebert, B. L.;
Gozo, M.; Cuker, A.; Wernig, G.; Moore, S.; Galinsky, I.; DeAngelo,
D. J.; Clark, J. J.; Lee, S. J.; Golub, T. R.; Wadleigh, M.; Gilliland,
D. G.; Levine, R. L.: MPLW515L is a novel somatic activating mutation
in myelofibrosis with myeloid metaplasia. PLoS Med. 3: e270, 2006.
Note: Electronic Article.

9. Sieff, C. A.; Malleson, P.: Familial myelofibrosis. Arch. Dis.
Child. 55: 888-893, 1980.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEMATOLOGY:
Myeloproliferative disease;
Reduced hemopoiesis;
Generalized bone marrow fibrosis;
No hemophagocytosis

MISCELLANEOUS:
Onset first weeks of life

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/10/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 1/7/2014
Marla J. F. O'Neill - updated: 6/10/2009
Cassandra L. Kniffin - updated: 3/27/2008
Victor A. McKusick - updated: 5/10/2005
Victor A. McKusick - updated: 2/24/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 02/07/2014
carol: 1/8/2014
ckniffin: 1/7/2014
carol: 11/14/2012
terry: 11/13/2012
ckniffin: 10/24/2011
wwang: 10/26/2010
ckniffin: 10/25/2010
wwang: 10/14/2009
ckniffin: 9/15/2009
wwang: 6/12/2009
terry: 6/10/2009
carol: 4/7/2008
ckniffin: 3/27/2008
tkritzer: 5/18/2005
tkritzer: 5/16/2005
terry: 5/10/2005
carol: 3/7/1999
terry: 2/24/1999
mimman: 2/8/1996
supermim: 3/17/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/4/1986

MIM 263300
*RECORD*
*FIELD* NO
263300
*FIELD* TI
#263300 POLYCYTHEMIA VERA; PV
;;POLYCYTHEMIA RUBRA VERA; PRV
*FIELD* TX
A number sign (#) is used with this entry because of evidence that most
read morecases of polycythemia vera (PV) are associated with a somatic mutation
in the JAK2 gene (147796) on chromosome 9p.

Somatic mutations in the TET2 gene (612839) and the NFE2 gene (601490)
have also been found in cases of polycythemia vera.

DESCRIPTION

Polycythemia vera, the most common form of primary polycythemia, is
caused by somatic mutation in a single hematopoietic stem cell leading
to clonal hematopoiesis. PV is a myeloproliferative disorder
characterized predominantly by erythroid hyperplasia, but also by
myeloid leukocytosis, thrombocytosis, and splenomegaly. Familial cases
of PV are very rare and usually manifest in elderly patients (Cario,
2005). PV is distinct from the familial erythrocytoses (see, e.g.,
ECYT1, 133100), which are caused by inherited mutations resulting in
hypersensitivity of erythroid progenitors to hormonal influences or
increased levels of circulating hormones, namely erythropoietin (EPO;
133170) (Prchal, 2005).

CLINICAL FEATURES

Owen (1924) emphasized the familial nature of polycythemia vera and
presented a possible example.

Modan (1965) suggested that in only 2 reports of familial PV was the
diagnosis completely documented (Lawrence and Goetsch, 1950; Erf, 1956).
Lawrence and Goetsch (1950) described 3 affected sibs. Two patients in
the series of Erf (1956) were brothers and 3 others had 'a definite
family history.' Modan (1965) found that polycythemia vera is more
frequent in Jews than in non-Jews in the United States, but shows no
simple mendelian pattern.

Levin et al. (1967) reported a curious case of 2 brothers with
polycythemia vera and the Philadelphia chromosome. Subsequently, this
was shown to be an instance of familial small Y chromosome (Levin,
1974).

Ratnoff and Gress (1980) described polycythemia vera in a father and
son, both of whom had had intermittent exposure to organic solvents,
including tetrachloroethylene and Stoddard solvent, which may have been
of etiologic significance. Although the authors found 3 other
well-substantiated familial occurrences of the disorder, none of them
encompassed successive generations.

Budd-Chiari syndrome (600880), characterized by obstruction and
occlusion of the suprahepatic veins, is a rare but typical complication
in polycythemia vera patients. Cario et al. (2003) described a third
pediatric case of Budd-Chiari syndrome as the initial symptom of
familial polycythemia vera in an 11-year-old girl; the patient's
grandmother also had polycythemia vera. The patient's mother was
unaffected. The patient underwent orthotopic liver transplantation and
the polycythemia vera was treated with hydroxyurea. In agreement with
the clinical diagnosis, the polycythemia rubra vera-1 gene (PRV1;
162860) showed increased mRNA expression in peripheral granulocytes.

In a review of familial polycythemia vera, Miller et al. (1989) included
31 patients from 13 families.

CYTOGENETICS

Chen et al. (1998) presented results indicating that amplification of a
gene or genes on 9p play a crucial role in the pathogenesis of PV. They
observed 2 cases of PV with an extra i(9)(p10) isochromosome as the sole
anomaly.

MOLECULAR GENETICS

Kralovics et al. (2003) studied 6 families with PV. The familial
predisposition was consistent with autosomal dominant inheritance with
incomplete penetrance. However, all affected individuals showed clonal
hematopoiesis, suggesting an acquired somatic nature of the disorder.
Kralovics et al. (2003) concluded that multiple genetic defects are
involved in PV.

Baxter et al. (2005) and Kralovics et al. (2005) found that 97% (71 of
73) and 65% (83 of 128) of patients with polycythemia vera,
respectively, carried a val617-to-phe mutation (V617F; 147796.0001) in
the JAK2 gene.

James et al. (2005) found that 88% (40 of 45) of patients with
polycythemia vera carried the V617F mutation in JAK2. They found that
the V617F mutation leads to constitutive tyrosine phosphorylation
activity that promotes cytokine hypersensitivity and induces
erythrocytosis in a mouse model.

In a 7-month-old girl with polycythemia vera, thrombocytosis, and
increased white cell count, Kelly et al. (2008) identified the V617F
mutation in blood but buccal cells, consistent with somatic mutation.
Due to the risk of malignant transformation, she underwent successful
allogeneic bone marrow transplantation. The findings indicated that the
mutation can occur at all ages, and Kelly et al. (2008) postulated a
prenatal somatic mutation in this patient.

Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow
cells from 320 patients with myeloid cancers and identified TET2 defects
in 13 patients with polycythemia vera, all of whom also displayed the
JAK2 V617F mutation.

Jutzi et al. (2013) identified 7 different somatic insertion or deletion
mutations in the NFE2 gene (601490) in 8 patients with
myeloproliferative disorders, including 3 with polycythemia vera and 5
with myelofibrosis (254450), either primary or secondary. In vitro
studies showed that the mutant truncated NFE2 proteins were unable to
bind DNA and had lost reporter gene activity. However, coexpression of
mutant NFE2 constructs with wildtype NFE2 resulted in significantly
enhanced transcriptional activity. Analysis of patient cells showed low
levels of the mutant truncated protein, but increased levels of the
wildtype NFE2 protein compared to control cells, likely due to both
increased mRNA and increased stability of the wildtype protein. All 7
patients tested also carried a JAK2 V617F mutation (147796.0001).
Hematopoietic cell colonies grown from 3 patients showed that the NFE2
mutation was acquired subsequent to the JAK2 mutation, and further
cellular studies indicated that an NFE2 mutation conferred a
proliferative advantage of cells compared to cells carrying only the
JAK2 mutation. Cells carrying mutant NFE2 displayed an increase in the
proportion of cells in the S phase, consistent with enhanced cell
division and proliferation, and this was associated with higher levels
of cell cycle regulators. These findings were replicated in mice
carrying NFE2 mutations, who developed thrombocytosis, erythrocytosis,
and neutrophilia.

PATHOGENESIS

Sozer et al. (2009) identified somatic homozygous JAK2 V617F mutations
in liver venule endothelial cells and hematopoietic cells from 2
unrelated PV patients who developed Budd-Chiari syndrome. However,
analysis of endothelial cells from a third PV patient with Budd-Chiari
syndrome and in 2 patients with hepatoportal sclerosis without PV showed
only wildtype JAK2. Endothelial and hematopoietic cells are believed to
come from a common progenitor called the hemangioblast. Sozer et al.
(2009) concluded that finding V617F-positive endothelial cells and
hematopoietic cells from PV patients who developed Budd-Chiari syndrome
indicates that endothelial cells are involved by the PV malignant
process, and suggested that the disease might originate from a common
cell of origin in some patients.

*FIELD* SA
Friedland et al. (1981); Manoharan and Garson (1976)
*FIELD* RF
1. Baxter, E. J.; Scott, L. M.; Campbell, P. J.; East, C.; Fourouclas,
N.; Swanton, S.; Vassiliou, G. S.; Bench, A. J.; Boyd, E. M.; Curtin,
N.; Scott, M. A.; Erber, W. N.; Cancer Genome Project; Green, A.
R.: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative
disorders. Lancet 365: 1054-1061, 2005. Note: Erratum: Lancet 366:
122 only, 2005.

2. Cario, H.: Childhood polycythemias/erythrocytoses: classification,
diagnosis, clinical presentation, and treatment. Ann. Hemat. 84:
137-145, 2005.

3. Cario, H.; Pahl, H. L.; Schwarz, K.; Galm, C.; Hoffmann, M.; Burdelski,
M.; Kohne, E.; Debatin, K.-M.: Familial polycythemia vera with Budd-Chiari
syndrome in childhood. Brit. J. Haemat. 123: 346-352, 2003.

4. Chen, Z.; Notohamiprodjo, M.; Guan, X.-Y.; Paietta, E.; Blackwell,
S.; Stout, K.; Turner, A.; Richkind, K.; Trent, J. M.; Lamb, A.; Sandberg,
A. A.: Gain of 9p in the pathogenesis of polycythemia vera. Genes
Chromosomes Cancer 22: 321-324, 1998.

5. Delhommeau, F.; Dupont, S.; Della Valle, V.; James, C.; Trannoy,
S.; Masse, A.; Kosmider, O.; Le Couedic, J.-P.; Robert, F.; Alberdi,
A.; Lecluse, Y.; Plo, I.; and 11 others: Mutation in TET2 in myeloid
cancers. New Eng. J. Med. 360: 2289-2301, 2009.

6. Erf, L. A.: Radioactive phosphorus in the treatment of primary
polycythemia. Prog. Hemat. 1: 153-165, 1956.

7. Friedland, M. L.; Wittels, E. G.; Robinson, R. J.: Polycythemia
vera in identical twins. Am. J. Hemat. 10: 101-103, 1981.

8. James, C.; Ugo, V.; Le Couedic, J.-P.; Staerk, J.; Delhommeau,
F.; Lacout, C.; Garcon, L.; Raslova, H.; Berger, R.; Bennaceur-Griscelli,
A.; Villeval, J. L.; Constantinescu, S. N.; Casadevall, N.; Vainchenker,
W.: A unique clonal JAK2 mutation leading to constitutive signalling
causes polycythaemia vera. Nature 434: 1144-1148, 2005.

9. Jutzi, J. S.; Bogeska, R.; Nikoloski, G.; Schmid, C. A.; Seeger,
T. S.; Stegelmann, F.; Schwemmers, S.; Grunder, A.; Peeken, J. C.;
Gothwal, M.; Wehrle, J.; Aumann, K.; Hamdi, K.; Dierks, C.; Wang,
W.; Dohner, K.; Jansen, J. H.; Pahl, H. L.: MPN patients harbor recurrent
truncating mutations in transcription factor NF-E2. J. Exp. Med. 210:
1003-1019, 2013.

10. Kelly, K.; McMahon, C.; Langabeer, S.; Eliwan, H.; O'Marcaigh,
A.; Smith, O. P.: Congenital JAK2-V617F polycythemia vera: where
does the genotype-phenotype diversity end? Blood 112: 4356-4357,
2008.

11. Kralovics, R.; Passamonti, F.; Buser, A. S.; Teo, S.-S.; Tiedt,
R.; Passweg, J. R.; Tichelli, A.; Cazzola, M.; Skoda, R. C.: A gain-of-function
mutation of JAK2 in myeloproliferative disorders. New Eng. J. Med. 352:
1779-1790, 2005.

12. Kralovics, R.; Stockton, D. W.; Prchal, J. T.: Clonal hematopoiesis
in familial polycythemia vera suggests the involvement of multiple
mutational events in the early pathogenesis of the disease. Blood 102:
3793-3796, 2003.

13. Lawrence, J. H.; Goetsch, A. T.: Familial occurrence of polycythemia
and leukemia. Calif. Med. 73: 361-364, 1950.

14. Levin, W. C.: Personal Communication. Galveston, Texas 1/9/1974.

15. Levin, W. C.; Houston, E. W.; Ritzmann, S. E.: Polycythemia vera
with Ph-1 chromosomes in two brothers. Blood 30: 503-512, 1967.

16. Manoharan, A.; Garson, O. M.: Familial polycythemia vera: a study
of three sisters. Scand. J. Haemat. 17: 10-16, 1976.

17. Miller, R. L.; Purvis, J. D., III; Welck, J. K.: Familial polycythemia
vera. Cleve. Clin. J. Med. 56: 813-818, 1989.

18. Modan, B.: Polycythemia: a review of epidemiological and clinical
aspects. J. Chronic Dis. 18: 605-645, 1965.

19. Owen, T.: A case of polycythaemia vera with special reference
to the familial features and treatment with phenylhydrazine. Johns
Hopkins Hosp. Bull. 35: 258-262, 1924.

20. Prchal, J. T.: Polycythemia vera and other primary polycythemias. Curr.
Opin. Hemat. 12: 112-116, 2005.

21. Ratnoff, W. D.; Gress, R. E.: The familial occurrence of polycythemia
vera: report of a father and son, with consideration of the possible
etiologic role of exposure to organic solvents, including tetrachloroethylene. Blood 56:
233-236, 1980.

22. Sozer, S.; Fiel, M. I.; Schiano, T.; Xu, M.; Mascarenhas, J.;
Hoffman, R.: The presence of JAK2V617F mutation in the liver endothelial
cells of patients with Budd-Chiari syndrome. Blood 113: 5246-5249,
2009.

*FIELD* CS
INHERITANCE:
Somatic mutation

CARDIOVASCULAR:
[Heart];
Myocardial ischemia;
[Vascular];
Thrombosis;
Thromboembolic events;
Cerebral ischemia;
Budd-Chiari syndrome

ABDOMEN:
[Spleen];
Splenomegaly;
[Gastrointestinal];
Gastrointestinal bleeding

NEUROLOGIC:
[Central nervous system];
Cerebral ischemia;
Cerebral hemorrhage

HEMATOLOGY:
Increased red blood cell mass;
Increased hemoglobin;
Increased hematocrit;
Increased myeloid precursor cells;
Increased megakaryocyte precursor cells;
Leukocytosis;
Thrombocytosis;
Thrombocytopenia

LABORATORY ABNORMALITIES:
Normal or decreased serum erythropoietin (EPO, 133170);
Increased PRV-1 (162860) mRNA;
Erythroid colony-forming units show spontaneous growth in the absence
of EPO;
Normal arterial oxygen saturation

MISCELLANEOUS:
Mean age at onset 57-60 years;
Children rarely develop the disorder;
Familial cases are rare and show incomplete penetrance;
Distinct disorder from familial erythrocytosis (ECYT1, 133100)

MOLECULAR BASIS:
Caused by somatic mutation in the janus kinase 2 gene (JAK2, 147796)

*FIELD* CN
Cassandra L. Kniffin - revised: 5/23/2006

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/25/2012
ckniffin: 7/14/2006
joanna: 7/3/2006
ckniffin: 5/23/2006

*FIELD* CN
Cassandra L. Kniffin - updated: 1/7/2014
Cassandra L. Kniffin - updated: 12/29/2009
Marla J. F. O'Neill - updated: 6/10/2009
Cassandra L. Kniffin - updated: 3/9/2009
Cassandra L. Kniffin - updated: 5/23/2006
Ada Hamosh - updated: 5/25/2005
Victor A. McKusick - updated: 5/10/2005
Victor A. McKusick - updated: 12/8/2003
Victor A. McKusick - updated: 11/4/1998

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 01/08/2014
ckniffin: 1/7/2014
terry: 11/13/2012
wwang: 1/13/2010
ckniffin: 12/29/2009
terry: 12/17/2009
wwang: 6/12/2009
terry: 6/10/2009
wwang: 3/18/2009
ckniffin: 3/9/2009
carol: 5/24/2006
ckniffin: 5/23/2006
tkritzer: 5/25/2005
terry: 5/25/2005
tkritzer: 5/18/2005
tkritzer: 5/16/2005
terry: 5/10/2005
terry: 11/4/2004
tkritzer: 12/17/2003
terry: 12/8/2003
carol: 5/8/2002
carol: 4/4/2001
carol: 11/12/1998
terry: 11/4/1998
alopez: 9/2/1998
terry: 6/18/1998
mimadm: 4/14/1994
supermim: 3/17/1992
supermim: 3/20/1990
carol: 12/9/1989
ddp: 10/27/1989
marie: 3/25/1988

MIM 600880
*RECORD*
*FIELD* NO
600880
*FIELD* TI
#600880 BUDD-CHIARI SYNDROME; BDCHS
MEMBRANOUS OBSTRUCTION OF INFERIOR VENA CAVA, INCLUDED; MOVC, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because susceptibility to
Budd-Chiari syndrome can result from mutation in the F5 gene (612309) on
chromosome 1q24 or somatic mutation in the JAK2 gene (147796) on
chromosome 9p24.

CLINICAL FEATURES

Budd-Chiari syndrome is a spectrum of disease states, including anatomic
abnormalities and hypercoagulable disorders, resulting in hepatic venous
outflow occlusion. Clinical manifestations observed in the majority of
patients include hepatomegaly, right upper quadrant pain, and abdominal
ascites (Zimmerman et al., 2006).

One of the causes of the Budd-Chiari syndrome is a membranous
obstruction of the inferior vena cava (MOVC). Primary thrombosis due to
a thrombophilia such as that resulting from defects in the natural
coagulation inhibitors such as protein C (612283), protein S (176880),
and antithrombin III (107300) are also causes. Riemens et al. (1995)
reported a family in which 3 of 11 sibs (2 sisters and 1 brother) showed
symptoms of MOVC developing in early adult life. All had signs of more
longstanding disease, as judged by the presence of collaterals,
cirrhosis, and, in one case, hepatocellular carcinoma. The brother died
with lung metastasis from the hepatocellular carcinoma, while the 2
sisters had surgical removal of the membrane and were well 20 and 21
years after surgery. On family screening, no further cases of membranous
obstruction of the inferior vena cava were found. There was no evidence
of an inherited defect in a coagulation inhibitor or plasminogen
deficiency (173350); however, Riemens et al. (1995) could not totally
exclude a thrombotic etiology.

Budd-Chiari syndrome is a rare but typical complication in patients with
polycythemia vera (PV; 263300). Cario et al. (2003) described a third
pediatric case of Budd-Chiari syndrome as the initial symptom of
familial polycythemia vera in an 11-year-old girl; the patient's
grandmother also had polycythemia vera. The patient's mother was
unaffected. The patient underwent orthotopic liver transplantation and
the polycythemia vera was treated with hydroxyurea. In agreement with
the clinical diagnosis, the polycythemia rubra vera-1 gene (PRV1;
162860) showed increased mRNA expression in peripheral granulocytes.

Menon et al. (2004) reviewed all aspects of Budd-Chiari syndrome,
including the inherited hypercoagulable states that had been found to be
associated with the disorder. They noted that the relative risk of
hepatic vein thrombosis among women who use oral contraceptives is 2.37,
which is similar to their relative risk of stroke, myocardial
infarction, and venous thromboembolism (Valla et al., 1986). Many
patients in whom Budd-Chiari syndrome develops in association with the
use of oral contraceptives or pregnancy also have an underlying
thrombophilia, either inherited or acquired.

MOLECULAR GENETICS

Mahmoud et al. (1997) reported the incidence of the factor V Leiden
mutation (R506Q; 612309.0001) in Budd-Chiari syndrome and portal vein
thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with
Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had
coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with
portal vein thrombosis was found to have the R506Q mutation. The
mutation was found in 3 (6%) of the 54 controls, who had liver disease
but no history of thrombophilia. Mahmoud et al. (1997) concluded that
the R506Q mutation seems to be an important factor in the pathogenesis
of Budd-Chiari syndrome but not of portal vein thrombosis.

Gurakan et al. (1999) described a child with Budd-Chiari syndrome who
was homozygous for the factor V Leiden mutation. Budd-Chiari syndrome is
rare in children.

Janssen et al. (2000) compared 43 patients with Budd-Chiari syndrome and
92 patients with portal vein thrombosis with 474 population-based
controls. The relative risk of Budd-Chiari syndrome was 11.3 for
individuals with the factor V Leiden mutation, 2.1 for those with a
prothrombin (176930) gene mutation, and 6.8 for those with protein C
deficiency. In patients with portal vein thrombosis, the corresponding
figures were 2.7, 1.4, and 4.6, respectively. The relative risk of
Budd-Chiari syndrome or portal vein thrombosis was not increased in the
presence of inherited protein S or antithrombin deficiency.

Patel (2005) identified a V617F mutation in the JAK2 gene (147796.0001)
in a high proportion of patients with the Budd-Chiari syndrome,
providing evidence that these patients have a latent myeloproliferative
disorder. Chung et al. (2006) described Budd-Chiari syndrome in a
46-year-old woman who was well until the onset of increasing abdominal
distention over a period of several days. She was found to have a
combination of the JAK2 V617F mutation and the factor V Leiden mutation.

PATHOGENESIS

Sozer et al. (2009) identified somatic homozygous JAK2 V617F mutations
in liver venule endothelial and hematopoietic cells from 2 unrelated
patients with polycythemia vera who developed Budd-Chiari syndrome.
However, analysis of endothelial cells from a third PV patient with
Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis
without PV showed only wildtype JAK2. Endothelial and hematopoietic
cells are believed to come from a common progenitor called the
hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive
endothelial cells and hematopoietic cells from patients with PV who
developed Budd-Chiari syndrome indicates that endothelial cells are
involved by the PV malignant process, and suggested that the disease
might originate from a common cell of origin in some patients.

*FIELD* RF
1. Cario, H.; Pahl, H. L.; Schwarz, K.; Galm, C.; Hoffmann, M.; Burdelski,
M.; Kohne, E.; Debatin, K.-M.: Familial polycythemia vera with Budd-Chiari
syndrome in childhood. Brit. J. Haemat. 123: 346-352, 2003.

2. Chung, R. T.; Iafrate, A. J.; Amrein, P. C.; Sahani, D. V.; Misdraji,
J.: Case 15-2006: a 46-year-old woman with sudden onset of abdominal
distention. New Eng. J. Med. 354: 2166-2175, 2006.

3. Gurakan, F.; Gurgey, A.; Bakkaloglu, A.; Kocak, N.: Homozygous
factor V Leiden mutation in a child with Budd-Chiari syndrome. J.
Pediat. Gastroent. Nutr. 28: 516-517, 1999.

4. Janssen, H. L. A.; Meinardi, J. R.; Vleggaar, F. P.; van Uum, S.
H. M.; Haagsma, E. B.; van der Meer, F. J. M.; van Hattum, J.; Chamuleau,
R. A. F. M.; Adang, R. P.; Vandenbroucke, J. P.; van Hoek, B.; Rosendaal,
F. R.: Factor V Leiden mutation, prothrombin gene mutation, and deficiencies
in coagulation inhibitors associated with Budd-Chiari syndrome and
portal vein thrombosis: results of a case-control study. Blood 96:
2364-2368, 2000.

5. Mahmoud, A. E. A.; Elias, E.; Beauchamp, N.; Wilde, J. T.: Prevalence
of the factor V Leiden mutation in hepatic and portal vein thrombosis. Gut 40:
798-800, 1997.

6. Menon, K. V. N.; Shah, V.; Kamath, P. S.: The Budd-Chiari syndrome. New
Eng. J. Med. 350: 578-585, 2004.

7. Patel, R. K.: Prevalence of the activating JAK2 tyrosine kinase
mutation V617F in the Budd-Chiari syndrome. Proceedings of the 47th
Annual Meeting of the American Society of Hematology. Atlanta: ,
12/10/2005. Note: P. 7282.

8. Riemens, S. C.; Haagsma, E. B.; Kok, T.; Gouw, A. S. H.; van der
Jagt, E. J.: Familial occurrence of membranous obstruction of the
inferior vena cava: arguments in favor of a congenital etiology. J.
Hepatol. 22: 404-409, 1995.

9. Sozer, S.; Fiel, M. I.; Schiano, T.; Xu, M.; Mascarenhas, J.; Hoffman,
R.: The presence of JAK2V617F mutation in the liver endothelial cells
of patients with Budd-Chiari syndrome. Blood 113: 5246-5249, 2009.

10. Valla, D.; Le, M. G.; Poynard, T.; Zucman, N.; Rueff, B.; Benhamou,
J. P.: Risk of hepatic vein thrombosis in relation to recent use
of oral contraceptives: a case-control study. Gastroenterology 90:
807-811, 1986.

11. Zimmerman, M. A.; Cameron, A. M.; Ghobrial, R. M.: Budd-Chiari
syndrome. Clin. Liver Dis. 10: 259-273, 2006.

*FIELD* CS

Vascular:
Membranous obstruction of inferior vena cava (MOVC);
Collateral veins

GI:
Cirrhosis

Oncology:
Hepatocellular carcinoma

Inheritance:
? Autosomal recessive

*FIELD* CN
Cassandra L. Kniffin - updated: 12/29/2009
Victor A. McKusick - updated: 2/24/2004
Victor A. McKusick - updated: 12/22/2003
Victor A. McKusick - updated: 1/9/2001
Paul Brennan - updated: 11/14/1997

*FIELD* CD
Victor A. McKusick: 10/19/1995

*FIELD* ED
carol: 03/23/2012
terry: 7/25/2011
carol: 7/19/2011
wwang: 1/13/2010
ckniffin: 12/29/2009
carol: 10/8/2008
carol: 2/9/2007
tkritzer: 2/27/2004
terry: 2/24/2004
tkritzer: 12/22/2003
alopez: 4/30/2001
mcapotos: 1/22/2001
mcapotos: 1/12/2001
terry: 1/9/2001
alopez: 12/5/1997
mark: 6/10/1997
mark: 12/13/1995
mimadm: 11/3/1995
mark: 10/19/1995

MIM 601626
*RECORD*
*FIELD* NO
601626
*FIELD* TI
#601626 LEUKEMIA, ACUTE MYELOID; AML
;;LEUKEMIA, ACUTE MYELOGENOUS
LEUKEMIA, ACUTE MYELOID, SUSCEPTIBILITY TO, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that acute
myeloid leukemia (AML) can be caused by mutations in the CEBPA gene
(116897) and the NPM1 gene (164040).

Somatic mutations in several genes have been found in cases of AML,
e.g., in the CEBPA, ETV6 (600618), JAK2 (147796), KRAS2 (190070), HIPK2
(606868), FLT3 (136351), TET2 (612839), ASXL1 (612990), IDH1 (147700),
CBL (165360), DNMT3A (602769), and SF3B1 (605590) genes. Other causes of
AML include fusion genes generated by chromosomal translocations; see,
for example, 600358 and 159555.

Susceptibility to the development of acute myeloid leukemia may be
caused by germline mutations in certain genes, including GATA2 (137295),
TERC (602322), and TERT (187270).

AML may also be part of the phenotypic spectrum of inherited disorders,
including platelet disorder with associated myeloid malignancy (FPDMM;
601399), caused by mutation in the RUNX1 gene (151385), and
telomere-related pulmonary fibrosis and/or bone marrow failure (PFBMFT1,
614742 and PFBMFT2, 614743), caused by mutation in the TERT or the TERC
gene.

CLINICAL FEATURES

Shields et al. (2003) published a case report on acute myeloid leukemia
that presented as bilateral orbital myeloid sarcoma (or chloroma) in a
previously healthy 25-month-old boy. Bone marrow biopsy revealed blasts
and cells with maturing monocytic features. A final diagnosis of M5b AML
was made. The authors reviewed the literature and concluded that
leukemia may be the most likely diagnosis in a child with bilateral soft
tissue orbital tumors.

CLINICAL MANAGEMENT

AML is often treated with allogeneic hematopoietic stem-cell
transplantation (HSCT), and it is most sensitive to natural killer
(NK)-cell reactivity. Venstrom et al. (2012) assessed clinical data, HLA
genotyping results, and donor cell lines or genomic DNA for 1,277
patients with AML who had received HSCT from unrelated donors matched
for HLA-A, -B, -C, -DR, and -DQ or with a single mismatch. They
performed donor KIR genotyping and evaluated the clinical effect of
donor KIR genotype and donor and recipient HLA genotypes. Patients with
AML who received allografts from donors who were positive for KIR2DS1
(604952) had a lower rate of relapse than those with allografts from
donors who were negative for KIR2DS1 (26.5% vs 32.5%; hazard ratio,
0.76; 95% confidence interval, 0.61 to 0.96; P = 0.02). Of allografts
from donors with KIR2DS1, those from donors who were homozygous or
heterozygous for HLA-C1 antigens could mediate this antileukemic effect,
whereas those from donors who were homozygous for HLA-C2 did not provide
any advantage. Recipients of KIR2DS1-positive allografts mismatched for
a single HLA-C locus had a lower relapse rate than recipients of
KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs
35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P = 0.007). KIR3DS1
(see 604946), in positive genetic linkage disequilibrium with KIR2DS1,
had no effect on leukemia relapse but was associated with decreased
mortality (60.1% vs 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI,
0.71 to 0.96; P = 0.01). Venstrom et al. (2012) concluded that
activating KIR genes from donors were associated with distinct outcomes
of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection
against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was
associated with reduced mortality.

BIOCHEMICAL FEATURES

Garzon et al. (2009) provided evidence supporting a tumor suppressor
role for miR29A (610782) and miR29B (610783) in AML. Overexpression of
both microRNAs reduced cell growth and induced apoptosis in AML cell
lines. Injection of miR29B in a xenograft mouse model of AML resulted in
tumor shrinkage. Northern blot analysis showed that the 2 microRNAs
targeted genes involved in apoptosis, the cell cycle, and cell
proliferation. Transfection of leukemic cells with miR29A and miR29B
resulted in specific downregulation of CXXC6 (TET1; 607790), MCL1
(159552), and CDK6 (603368). Studies of 45 samples from patients with
AML showed an inverse correlation between MCL1 and miR29B. Although 42%
of the miR29A-correlated genes were also correlated with miR29B, there
were some differences: genes related to protein metabolism were found
overrepresented in miR29B-correlated genes, and genes related to immune
function were overrepresented in miR29A-correlated genes. Finally, there
was a downregulation of both miR29A and miR29B in primary AML samples
with monosomy 7 (252270).

CYTOGENETICS

Loss of chromosome 5q is observed in 10 to 15% of patients with
myelodysplastic syndrome (MDS) or acute myeloid leukemia and in 40% of
patients with therapy-related MDS or AML. In addition, patients with 5q
deletion syndrome (153550) show hematologic abnormalities, including
refractory anemia and abnormal megakaryocytes. By cytogenetic analysis
and hybridization techniques, Le Beau et al. (1993) identified a common
2.8-Mb critical region containing the EGR1 gene (128990) on chromosome
5q31 that was deleted in 135 patients with hematologic abnormalities and
5q deletions, including 85 patients with de novo MDS or AML, 33 with
therapy-related MDS or AML, and 17 with MDS and the 5q deletion
syndrome. Le Beau et al. (1993) postulated that EGR1 or another
closely-linked gene may act as a tumor suppressor gene.

Baozhang et al. (1999) reported a family with 7 cases of related
leukemias among 22 members in 3 consecutive generations consistent with
autosomal dominant inheritance. One of the patients and her father were
found to have rearrangement and a rearrangement/amplification,
respectively, of the ERBB oncogene (131550).

Horwitz et al. (1996) reported evidence of anticipation in familial
acute myelogenous leukemia. Horwitz et al. (1996) further studied those
pedigrees and others from the literature. In 49 affected individuals
from 9 families transmitting autosomal dominant AML, the mean age of
onset was 57 years in the grandparental generation, 32 years in the
parental generation, and 13 years in the youngest generation (p less
than 0.001). Horwitz et al. (1996) also reported evidence of
anticipation in autosomal dominant chronic lymphocytic leukemia (CLL;
151400) (p = 0.008). In 18 affected individuals from 7 pedigrees with
autosomal dominant CLL, the mean age of onset in the parental generation
was 66 years, versus 51 years in the younger generation. Based on this
evidence of anticipation, Horwitz et al. (1996) suggested that dynamic
mutations of unstable DNA sequence repeats could be a common mechanism
of inherited hematopoietic malignancy. They proposed 3 possible
candidate chromosomal regions for familial leukemia with anticipation:
21q22.1-22.2, 11q23.3 in the vicinity of the CBL2 gene (165360), and
16q22 in the vicinity of the CBFB gene (121360).

MAPPING

Horwitz et al. (1997) presented evidence suggesting that there is a
locus for acute myelogenous leukemia on chromosome 16q22. They studied a
family with 11 relevant meioses transmitting autosomal dominant AML and
myelodysplasia. They excluded linkage to 21q22.1-q22.2 and to 9p22-p21,
and found a maximum 2-point lod score of 2.82 with the microsatellite
marker D16S522 at recombination fraction theta = 0.0. Haplotype analysis
showed a 23.5-cM region of 16q22 that was inherited in common by all
affected family members and extended from D16S451 to D16S289.
Nonparametric linkage analysis gave a p value of 0.00098 for the
conditional probability of linkage. Mutation analysis excluded expansion
of the AT-rich minisatellite repeat FRA16B fragile site and the CAG
trinucleotide repeat in the E2F-4 transcription factor (600659). The
'repeat expansion detection' method, capable of detecting dynamic
mutation associated with anticipation, more generally excluded large CAG
repeat expansion as a cause of leukemia in this family.

MOLECULAR GENETICS

- Mutations in CEBPA

In affected members of a family with acute myeloid leukemia, Smith et
al. (2004) identified a germline 1-bp deletion (212delC; 116897.0007) in
the CEBPA gene. Overt leukemia developed in the father at age 10 years,
in the first-born son at age 30 years, and in the last-born daughter at
age 18 years.

- Mutations in NPM1

NPM, a nucleocytoplasmic shuttling protein with prominent nucleolar
localization, regulates the ARF (103180)/p53 (191170) tumor suppressor
pathway. Chromosomal translocations involving the NPM gene cause
cytoplasmic dislocation of the NPM protein. Falini et al. (2005) used
immunohistochemical methods to study the subcellular localization of NPM
in bone marrow biopsy specimens from 591 patients with primary AML. They
then correlated the presence of cytoplasmic NPM with clinical and
biologic features of the disease. Cytoplasmic NPM was detected in 35.2%
of the 591 specimens from patients with primary AML but not in 135
secondary AML (sAML) specimens or in 980 hematopoietic or
extrahematopoietic neoplasms other than AML. It was associated with a
wide spectrum of morphologic subtypes of the disease, a normal
karyotype, and responsiveness to induction chemotherapy, but not with
recurrent genetic abnormalities. There was a high frequency of internal
tandem duplications of FLT3 (136351) and absence of CD34 (142230) and
CD133 (604365) in AML specimens with a normal karyotype and cytoplasmic
dislocation of NPM, but not in those in which the protein was restricted
to the nucleus. AML specimens with cytoplasmic NPM carried mutations in
the NPM gene (see 164040.0001-164040.0004); this mutant gene caused
cytoplasmic localization of NPM in transfected cells. All 6 NPM mutant
proteins showed mutations in at least 1 of the tryptophan residues at
positions 288 and 290 and shared the same last 5 amino acid residues
(VSLRK). Thus, despite genetic heterogeneity, all NPM gene mutations
resulted in a distinct sequence in the NPM protein C terminus. Falini et
al. (2005) concluded that cytoplasmic NPM is a characteristic feature of
a large subgroup of patients with AML who have a normal karyotype, NPM
gene mutations, and responsiveness to induction chemotherapy. Grisendi
and Pandolfi (2005) noted that NPM staining in cases of AML with
aberrant cytoplasmic localization of the protein is mostly cytoplasmic,
which suggests that the mutant NPM acts dominantly on the product of the
remaining wildtype allele, causing its retention in the cytoplasm by
heterodimerization.

By microRNA (miRNA) expression profiling, Garzon et al. (2008)
identified 36 upregulated and 21 downregulated miRNAs in AML patients
with NPM1 mutations compared with AML patients without NPM1 mutations.
miR10A (MIRN10A; 610173) and miR10B (MIRN10B; 611576) showed the
greatest upregulation, with increases of 20- and 16.67-fold,
respectively. Mir22 (MIRN22; 612077) showed greatest downregulation,
with a reduction of 0.31-fold. Garzon et al. (2008) concluded that AML
with NPM1 mutations has a distinctive miRNA signature.

- Mutations in GATA2

Hahn et al. (2011) analyzed 50 candidate genes in 5 families with a
predisposition to myelodysplastic syndrome (614286) and acute myeloid
leukemia, and in 3 of the families they identified a heritable
heterozygous missense mutation in the GATA2 gene (T354M; 137295.0002)
that segregated with disease and was not found in 695 nonleukemic
ethnically matched controls.

- Mutations in TERT

Calado et al. (2009) found a significantly increased number of germline
mutations in the TERT gene in patients with sporadic acute myeloid
leukemia compared to controls. One mutation in particular, A1062T
(187270.0022), was 3-fold higher among 594 AML patients compared to
1,110 controls (p = 0.0009). In vitro studies showed that the mutations
caused haploinsufficiency of telomerase activity. An abnormal karyotype
was found in 18 of 21 patients with TERT mutations who were tested.
Calado et al. (2009) suggested that telomere attrition may promote
genomic instability and DNA damage, which may contribute to the
development of leukemia.

- Somatic Mutations

In the bone marrow of a 4-year-old child with AML, Bollag et al. (1996)
identified an insertion in the KRAS2 gene (190070.0008). Expression
studies showed that the mutant KRAS2 protein caused cellular
transformation and activated the RAS-mitogen-activated protein kinase
signaling pathway.

Bone marrow minimal residual disease causes relapse after chemotherapy
in patients with acute myelogenous leukemia. Matsunaga et al. (2003)
postulated that the drug resistance is induced by the attachment of very
late antigen-4 (VLA4; see 192975) on leukemic cells to fibronectin
(135600) on bone marrow stromal cells. Matsunaga et al. (2003) found
that VLA4-positive cells acquired resistance to anoikis (loss of
anchorage) or drug-induced apoptosis through the
phosphatidylinositol-3-kinase (see 601232)/AKT (164730)/Bcl2 (151430)
signaling pathway, which is activated by the interaction of VLA4 and
fibronectin. This resistance was negated by VLA4-specific antibodies. In
a mouse model of minimal residual disease, Matsunaga et al. (2003)
achieved a 100% survival rate by combining VLA4-specific antibodies and
cytosine arabinoside, whereas cytosine arabinoside alone prolonged
survival only slightly. In addition, overall survival at 5 years was
100% for 10 VLA4-negative patients and 44.4% for 15 VLA4-positive
patients. Thus, Matsunaga et al. (2003) concluded that the interaction
between VLA4 on leukemic cells and fibronectin on stromal cells may be
crucial in bone marrow minimal residual disease and AML prognosis.

Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2005) analyzed 300
patients newly diagnosed with AML for mutations in the coding region of
the ETV6 gene and identified 5 somatic heterozygous mutations (e.g.,
600618.0001 and 600618.0002). These ETV6 mutant proteins were unable to
repress transcription and showed dominant-negative effects. The authors
also examined ETV6 protein expression in 77 patients with AML and found
that 24 (31%) lacked the wildtype 57- and 50-kD proteins; there was no
correlation between ETV6 mRNA transcript levels and the loss of ETV6
protein, suggesting posttranscriptional regulation of ETV6.

Lee et al. (2006) identified heterozygosity for mutations in the JAK2
gene (147796.0001 and 147796.0002) in bone marrow aspirates from 3
(2.7%) of 113 unrelated patients with AML.

Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow
cells from 320 patients with myeloid cancers and identified TET2 defects
in 2 patients with primary AML and 5 patients with secondary AML.

Mardis et al. (2009) used massively parallel DNA sequencing to obtain a
very high level of coverage of a primary, cytogenetically normal, de
novo genome for AML with minimal maturation (AML-M1) and a matched
normal skin genome. Mardis et al. (2009) identified 12 somatic mutations
within the coding sequences of genes and 52 somatic point mutations in
conserved or regulatory portions of the genome. All mutations appeared
to be heterozygous and present in nearly all cells in the tumor sample.
Four of the 64 mutations occurred in at least 1 additional AML sample in
188 samples that were tested. Mutations in NRAS (164790) and NPM1
(164040) had been previously identified in patients with AML, but 2
other mutations had not been identified. One of these mutations, in the
IDH1 (147700) gene, was present in 15 of 187 additional AML genomes
tested and was strongly associated with normal cytogenetic status; it
was present in 13 of 80 cytogenetically normal samples (16%). The other
was a nongenic mutation in a genomic region with regulatory potential
and conservation in higher mammals; it is at position 108,115,590 of
chromosome 10. The AML genome that was sequenced contained approximately
750 point mutations, of which only a small fraction are likely to be
relevant to pathogenesis.

Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene
(612990) may act as a tumor suppressor in myeloid malignancies. They
identified heterozygous somatic mutations in the ASXL1 gene in 5 (16%)
of 38 myelodysplastic syndrome/acute myeloid leukemia samples. Somatic
ASXL1 mutations were also found in 19 (43%) of 44 chronic myelomonocytic
leukemia (CMML; see 607785) samples. All the mutations were in exon 12
and resulted in truncation of the C-terminal PHD finger of the protein.
The findings suggested that regulators of gene expression via DNA
methylation, histone modification, and chromatin remodeling could be
altered in myelodysplastic syndromes and some leukemias. The same group
(Carbuccia et al., 2009) identified heterozygous somatic truncating
ASXL1 mutations in 5 (7.8%) of 64 myeloproliferative neoplasms,
including 1 essential thrombocythemia (187950), 3 primary myelofibrosis
(254450), and 1 AML.

Harutyunyan et al. (2011) analyzed biopsy specimens of
myeloproliferative neoplastic tissue from 330 patients for chromosomal
aberrations associated with leukemic transformation. Three hundred and
eight of the patients had chronic-phase myeloproliferative neoplasms and
22 had postmyeloproliferative-phase neoplasm secondary acute myeloid
leukemia. Among those 22 patients, 1 carried the MPL W515L mutation and
all others carried the JAK2 V617F mutation. Six of the 22 patients
carried somatic mutations of TP53 (191170). Three of the patients had
independent mutations on both TP53 alleles, and 2 had homozygous
mutations because of an acquired uniparental disomy of chromosome 17p.
None of the patients with TP53 mutations had amplification of chromosome
1q involving the MDM4 gene (604704). Harutyunyan et al. (2011) concluded
that TP53 mutations are strongly associated with transformation to AML
in patients with myeloproliferative neoplasms (p = 0.003). Harutyunyan
et al. (2011) also found amplification of a region of chromosome 1q
harboring the MDM4 gene in 18.18% of patients with secondary AML (p less
than 0.001).

Ding et al. (2012) determined the mutational spectrum associated with
relapse of AML by sequencing the primary tumor and relapse genomes from
8 AML patients, and validated hundreds of somatic mutations using deep
sequencing. This method allowed them to define clonality and clonal
evolution patterns precisely at relapse. In addition to discovering
novel, recurrently mutated genes (e.g., WAC; SMC3, 606062; DIS3, 607533;
DDX41, 608170; and DAXX, 603186) in AML, Ding et al. (2012) identified 2
major clonal evolution patterns during AML relapse: (1) the founding
clone in the primary tumor gained mutations and evolved into the relapse
clone, or (2) a subclone of the founding clone survived initial therapy,
gained additional mutations, and expanded at relapse. In all cases,
chemotherapy failed to eradicate the founding clone. The comparison of
relapse-specific versus primary tumor mutations in all 8 cases revealed
an increase in transversions, probably due to DNA damage caused by
cytotoxic chemotherapy. Ding et al. (2012) concluded that AML relapse is
associated with the addition of new mutations and clonal evolution,
which is shaped, in part, by the chemotherapy that the patients receive
to establish and maintain remissions.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. A total of 23 genes were significantly mutated, and another
237 were mutated in 2 or more samples. Nearly all samples had at least 1
nonsynonymous mutation in 1 of 9 categories of genes that were deemed
relevant for pathogenesis. The authors identified recurrent mutations in
the NPM1 gene in 54/200 (27%) samples, in the FLT3 gene (136351) in
56/200 (28%) samples, in the DNMT3A gene (602769) in 51/200 (26%)
samples, and in the IDH1 or IDH2 (147650) genes in 39/200 (20%) samples.

Brewin et al. (2013) noted that the study of the Cancer Genome Atlas
Research Network (2013) did not reveal which mutations occurred in the
founding clone, as would be expected for an initiator of disease, and
which occurred in minor clones, which subsequently drive disease. Miller
et al. (2013) responded that genes mutated almost exclusively in
founding clones in their study included RUNX1 (151385) (9 of 9 mutations
in founding clones), NPM1 (164040) (3 of 3 clones), U2AF1 (191317) (5 of
5 clones), DNMT3A (38 of 40 clones), IDH2 (13 of 14), IDH1 (147700) (15
of 17 clones), and KIT (164920) (5 of 6). In contrast, mutations in
NRAS, TET2 (612839), CEBPA, WT1 (607102), PTPN11 (176876), and FLT3 were
often found in subclones, suggesting that they were often cooperating
mutations.

GENOTYPE/PHENOTYPE CORRELATIONS

Schlenk et al. (2008) studied 872 patients younger than 60 years of age
with cytogenetically normal AML and compared mutation status of the NPM1
(164040), FLT3 (136351), CEBPA (116897), MLL (159555), and NRAS (164790)
genes in leukemia cells with clinical outcome. There was an overall
complete remission rate of 77%. The genotype of mutant NPM1 without FLT3
internal tandem duplications (FLT3-ITD), the mutant CEBPA genotype, and
younger age were each significantly associated with complete remission.
The authors also found that the benefit of postremission hematopoietic
stem cell transplant was limited to the subgroup of patients with the
prognostically adverse genotype FLT3-ITD or the genotype consisting of
wildtype NPM1 and CEBPA without FLT3-ITD.

Gale et al. (2008) found that 354 (26%) of 1,425 patients with AML had
the FLT3 internal duplication. The median total mutant level for all
patients was 35% of total FLT3, but there was wide variation with levels
ranging from 1 to 96%. There was a significant correlation between worse
overall survival, relapse risk, and increased white blood cell count
with increased mutant level, but the size of the duplication and the
number of mutations had no significant impact on outcome. Those patients
with the FLT3 duplication had a worse risk of relapse than patients
without the FLT3 duplication. Among a subset of 1,217 patients, 503
(41%) had a mutation in the NPM1 gene (164040), and 208 (17%) had
mutations in both genes. The presence of an NPM1 mutation had a
beneficial effect on the remission rate, most likely due to a lower rate
of resistant disease, both in patients with and without FLT3
duplications. Gale et al. (2008) identified 3 prognostic groups among
AML patients: good in those with only a NPM1 mutation; intermediate in
those with either no FLT3 or NPM1 mutations or mutations in both genes;
and poor in those with only FLT3 mutations.

Boissel et al. (2011) reviewed the work of several others and performed
their own analysis of 205 patients with cytogenetically normal AML, and
found that patients with IDH2(R172) mutations had a worse prognosis from
those with IDH2(R140) mutations (e.g., 147650.0001). That patients with
IDH2(R172) mutations had an unfavorable prognosis by comparison had been
noted by Marcucci et al. (2010). The frequency of IDH2(R172) mutations
was lower than that of IDH2(R140) mutations among cytogenetically normal
AML patients. Boissel et al. (2011) cautioned that patients should be
separated by mutation status for prognostic analysis.

Activating internal tandem duplication (ITD) mutations in FLT3
(FLT3-ITD) are detected in approximately 20% of acute myeloid leukemia
patients and are associated with a poor prognosis. Abundant laboratory
and clinical evidence, including the lack of convincing clinical
activity of early FLT3 inhibitors, suggested that FLT3-ITD probably
represents a passenger lesion. Smith et al. (2012) reported point
mutations at 3 residues within the kinase domain of FLT3-ITD that confer
substantial in vitro resistance to AC220 (quizartinib), an active
investigational inhibitor of FLT3, KIT (164920), PDGFRA (173490), PDGFRB
(173410), and RET (164761); evolution of AC220-resistant substitutions
at 2 of these amino acids was observed in 8 of 8 FLT3-ITD-positive AML
patients with acquired resistance to AC220. Smith et al. (2012)
concluded that their findings demonstrated that FLT3-ITD can represent a
driver lesion and valid therapeutic target in human AML.

ANIMAL MODEL

Jin et al. (2006) found that treatment with activating monoclonal
antibodies to CD44 (107269) markedly reduced leukemic repopulation in
nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice
challenged with human AML cells. Absence of leukemia following serial
tumor transplantation experiments in mice demonstrated direct targeting
of AML leukemic stem cells (LSCs). Treatment of engrafted mice with
anti-CD44 reduced the number of Cd34 (142230)-positive/Cd38
(107270)-negative primitive stem cells and increased the number of Cd14
(158120)-positive monocytic cells. Anti-CD44 treatment also diminished
the homing capacity of SCID leukemia-initiating cells to bone marrow and
spleen. Jin et al. (2006) concluded that CD44 is a key regulator of AML
LSCs, which require a niche to maintain their stem cell properties. They
suggested that CD44 targeting may help eliminate quiescent AML LSCs.

Mullican et al. (2007) generated Nr4a1 (139139)/Nr4a3 (600542)
double-null mice and observed the development of rapidly lethal acute
myeloid leukemia involving abnormal expansion of hematopoietic stem
cells and myeloid progenitors, decreased expression of JunB (165161) and
c-Jun (165160), and defective extrinsic apoptotic signaling (FASL,
134638; TRAIL, 603598). Leukemic blast cells from 46 AML patients with a
variety of cytogenetic abnormalities all showed downregulation of NR4A1
and NR4A3 compared to CD34+ cells from normal controls, suggesting that
epigenetic silencing of these receptors may be an obligate event in
human AML development.

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*FIELD* CS

Heme:
Familial acute myelogenous leukemia (AML)

Misc:
Evidence of anticipation;
Mean onset age 57 years, 32 years and 13 years in successive generations

Inheritance:
Autosomal dominant

*FIELD* CD
John F. Jackson: 09/23/1998

*FIELD* CN
Ada Hamosh - updated: 11/25/2013
Ada Hamosh - updated: 7/9/2013
Ada Hamosh - updated: 9/6/2012
Cassandra L. Kniffin - updated: 8/2/2012
Ada Hamosh - updated: 6/27/2012
Ada Hamosh - updated: 2/8/2012
Marla J. F. O'Neill - updated: 11/2/2011
Ada Hamosh - updated: 10/4/2011
Cassandra L. Kniffin - updated: 5/4/2011
Ada Hamosh - updated: 2/15/2011
Cassandra L. Kniffin - updated: 12/16/2010
Cassandra L. Kniffin - updated: 10/6/2009
Ada Hamosh - updated: 9/15/2009
Marla J. F. O'Neill - updated: 6/10/2009
Cassandra L. Kniffin - updated: 7/30/2008
Patricia A. Hartz - updated: 6/9/2008
Marla J. F. O'Neill - updated: 5/14/2008
Cassandra L. Kniffin - updated: 3/26/2008
Marla J. F. O'Neill - updated: 7/2/2007
Paul J. Converse - updated: 11/17/2006
Cassandra L. Kniffin - updated: 6/20/2006
Marla J. F. O'Neill - updated: 4/12/2006
Ada Hamosh - updated: 8/26/2003
Victor A. McKusick - updated: 11/17/1999

*FIELD* CD
Moyra Smith: 1/14/1997

*FIELD* ED
carol: 12/06/2013
alopez: 11/25/2013
alopez: 7/9/2013
alopez: 4/15/2013
alopez: 9/10/2012
terry: 9/6/2012
carol: 8/6/2012
ckniffin: 8/2/2012
alopez: 7/3/2012
terry: 6/27/2012
alopez: 2/10/2012
terry: 2/8/2012
carol: 1/30/2012
carol: 11/2/2011
ckniffin: 10/24/2011
alopez: 10/11/2011
terry: 10/7/2011
terry: 10/4/2011
wwang: 5/19/2011
wwang: 5/11/2011
ckniffin: 5/4/2011
ckniffin: 5/2/2011
alopez: 2/17/2011
terry: 2/15/2011
carol: 12/16/2010
ckniffin: 12/16/2010
carol: 7/2/2010
alopez: 1/28/2010
wwang: 10/14/2009
ckniffin: 10/6/2009
alopez: 9/16/2009
terry: 9/15/2009
wwang: 6/12/2009
terry: 6/10/2009
ckniffin: 6/9/2009
wwang: 12/5/2008
ckniffin: 12/3/2008
mgross: 10/9/2008
wwang: 8/1/2008
ckniffin: 7/30/2008
mgross: 6/9/2008
carol: 5/14/2008
wwang: 4/8/2008
ckniffin: 3/26/2008
wwang: 7/5/2007
terry: 7/2/2007
ckniffin: 3/1/2007
mgross: 11/17/2006
wwang: 6/23/2006
ckniffin: 6/20/2006
wwang: 4/12/2006
terry: 4/12/2006
mgross: 5/17/2005
tkritzer: 2/7/2005
alopez: 9/2/2003
alopez: 8/26/2003
terry: 8/26/2003
carol: 11/13/2001
mgross: 12/6/1999
terry: 11/17/1999
mark: 1/14/1997

MIM 614521
*RECORD*
*FIELD* NO
614521
*FIELD* TI
#614521 THROMBOCYTHEMIA 3; THCYT3
;;THROMBOCYTOSIS 3
*FIELD* TX
A number sign (#) is used with this entry because thrombocythemia-3
read more(THCYT3) is caused by heterozygous germline or somatic mutation in the
JAK2 gene (147796) on chromosome 9p24.

DESCRIPTION

Thrombocythemia-3 is an autosomal dominant hematologic disorder
characterized by increased platelet production resulting in increased
numbers of circulating platelets. Thrombocythemia can be associated with
thrombotic episodes, such as cerebrovascular events or myocardial
infarction (summary by Mead et al., 2012).

For a discussion of genetic heterogeneity of thrombocythemia, see THCYT1
(187950).

CLINICAL FEATURES

Mead et al. (2012) reported a 3-generation family with autosomal
dominant inheritance of thrombocythemia. The proband presented at age 53
years with an ischemic cerebrovascular event associated with
long-standing thrombocytosis (700 x 10(9) to 970 x 10(9)). There were 5
additional family members with thrombocytosis, including 1 with a
myocardial infarction at age 46 and another with a myocardial infarction
at age 65 and an ischemic cerebrovascular event at age 72. Bone marrow
biopsy showed megakaryocyte hyperplasia without fibrosis. In addition,
none of the patients had splenomegaly or evidence of leukemic
transformation.

INHERITANCE

The transmission pattern of thrombocythemia in the family reported by
Mead et al. (2012) was consistent with autosomal dominant inheritance.

MOLECULAR GENETICS

- Germline Mutation in the JAK2 Gene

In affected members of a family with thrombocythemia, Mead et al. (2012)
identified a germline heterozygous gain-of-function mutation in the JAK2
gene (V617I; 147796.0004). Examination of peripheral blood cells showed
normal baseline STAT3 (102582) activity and lack of cytokine-independent
colony formation. However, after stimulation with granulocyte
colony-stimulating factor (GCSF; 138970), V617I-containing CD33+ myeloid
and CD34+ stem cells showed a marked increase in STAT3 levels,
particularly in response to low levels of GCSF, suggesting that the
mutation causes limited constitutive activation with a reduced threshold
for cytokine-induced activation.

- Somatic Mutation in the JAK2 Gene

Baxter et al. (2005) and Kralovics et al. (2005) found that 57% (29 of
51) and 23% (21 of 93) of patients with essential thrombocytopenia,
respectively, carried a somatic mutation in the JAK2 gene (V617F;
147796.0001).

In a 45-year-old man with no cardiovascular risk factors who presented
in cardiogenic shock and was found to have coronary occlusion,
myocardial infarction, and multiple myocardial microthrombi, Lata et al.
(2010) identified at least 1 mutated V617F JAK2 allele on a peripheral
blood smear. The patient, who had a platelet count of 529,000 per cubic
millimeter, died in irreversible asystole after multiple percutaneous
transluminal coronary angioplasties, stenting, and intracoronary
fibrinolysis. Considering this to represent a fulminant initial
presentation of occult essential thrombocythemia, Lata et al. (2010)
stated that screening for the JAK2 mutation would likely be of value in
selected patients with otherwise unexplained coronary ischemic events
and mild thrombocytosis.

*FIELD* SA
Fialkow et al. (1981); Gaetani et al. (1982); Singal et al. (1983)
*FIELD* RF
1. Baxter, E. J.; Scott, L. M.; Campbell, P. J.; East, C.; Fourouclas,
N.; Swanton, S.; Vassiliou, G. S.; Bench, A. J.; Boyd, E. M.; Curtin,
N.; Scott, M. A.; Erber, W. N.; Cancer Genome Project; Green, A. R.
: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative
disorders. Lancet 365: 1054-1061, 2005. Note: Erratum: Lancet 366:
122 only, 2005.

2. Fialkow, P. J.; Faguet, G. B.; Jacobson, R. J.; Vaidya, K.; Murphy,
S.: Evidence that essential thrombocythemia is a clonal disorder
with origin in a multipotent stem cell. Blood 58: 916-919, 1981.

3. Gaetani, G. F.; Ferraris, A. M.; Galiano, S.; Giuntini, P.; Canepa,
L.; d'Urso, M.: Primary thrombocythemia: clonal origin of platelets,
erythrocytes, and granulocytes in a Gd(B)-Gd(Mediterranean) subject. Blood 59:
76-79, 1982.

4. Kralovics, R.; Passamonti, F.; Buser, A. S.; Teo, S.-S.; Tiedt,
R.; Passweg, J. R.; Tichelli, A.; Cazzola, M.; Skoda, R. C.: A gain-of-function
mutation of JAK2 in myeloproliferative disorders. New Eng. J. Med. 352:
1779-1790, 2005.

5. Lata, K.; Madiraju, N.; Levitt, L.: JAK2 mutations and coronary
ischemia. (Letter) New. Eng. J. Med. 363: 396-397, 2010.

6. Mead, A. J.; Rugless, M. J.; Jacobsen, S. E. W.: Schuh, A.: Germline
JAK2 mutation in a family with hereditary thrombocytosis. (Letter) New
Eng. J. Med. 366: 967-969, 2012.

7. Singal, U.; Prasad, A. S.; Halton, D. M.; Bishop, C.: Essential
thrombocythemia: a clonal disorder of hematopoietic stem cell. Am.
J. Hemat. 14: 193-196, 1983.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Somatic mutation

CARDIOVASCULAR:
[Heart];
Myocardial infarction, increased risk of;
[Vessels];
Cerebrovascular events, increased risk of

HEMATOLOGY:
Thrombocythemia;
Increased megakaryocytes in bone marrow

MISCELLANEOUS:
Germline or somatic mutations may cause the disorder;
Increased risk of myeloproliferative disorders in those with somatic
mutations

MOLECULAR BASIS:
Caused by mutation in the janus kinase 2 gene (JAK2, 147796.0001)

*FIELD* CD
Cassandra L. Kniffin: 3/8/2012

*FIELD* ED
joanna: 03/09/2012
ckniffin: 3/8/2012

*FIELD* CD
Cassandra L. Kniffin: 3/8/2012

*FIELD* ED
terry: 11/13/2012
terry: 3/9/2012
carol: 3/9/2012
ckniffin: 3/8/2012

RBCC Red Blood Cell Collection

Full text data of JAK2