RBCC Red Blood Cell Collection

ETV6 (TEL, TEL1) [Confidence: low (only semi-automatic identification from reviews)]
Transcription factor ETV6 (ETS translocation variant 6; ETS-related protein Tel1; Tel)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P41212
ID ETV6_HUMAN Reviewed; 452 AA.
AC P41212; A3QVP6; A8K076; Q9UMF6; Q9UMF7; Q9UMG0;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1995, sequence version 1.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Transcription factor ETV6;
DE AltName: Full=ETS translocation variant 6;
DE AltName: Full=ETS-related protein Tel1;
DE Short=Tel;
GN Name=ETV6; Synonyms=TEL, TEL1;
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=8168137; DOI=10.1016/0092-8674(94)90322-0;
RA Golub T.R., Barker G.F., Lovett M., Gilliland D.G.;
RT "Fusion of PDGF receptor beta to a novel ets-like gene, tel, in
RT chronic myelomonocytic leukemia with t(5;12) chromosomal
RT translocation.";
RL Cell 77:307-316(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Urinary bladder;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 56-109; 111-336 AND 338-452.
RX PubMed=8743990;
RA Baens M., Peeters P., Guo C., Aerssens J., Marynen P.;
RT "Genomic organization of TEL: the human ETS-variant gene 6.";
RL Genome Res. 6:404-413(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 56-452, AND CHROMOSOMAL TRANSLOCATION
RP WITH PAX5.
RX PubMed=17344859; DOI=10.1038/nature05690;
RA Mullighan C.G., Goorha S., Radtke I., Miller C.B., Coustan-Smith E.,
RA Dalton J.D., Girtman K., Mathew S., Ma J., Pounds S.B., Su X.,
RA Pui C.-H., Relling M.V., Evans W.E., Shurtleff S.A., Downing J.R.;
RT "Genome-wide analysis of genetic alterations in acute lymphoblastic
RT leukaemia.";
RL Nature 446:758-764(2007).
RN [7]
RP CHROMOSOMAL TRANSLOCATION WITH AML1.
RX PubMed=7761424; DOI=10.1073/pnas.92.11.4917;
RA Golub T.R., Barker G.F., Bohlander S.K., Hiebert S.W., Ward D.C.,
RA Bray-Ward P., Morgan E., Raimondi S.C., Rowley J.D., Gilliland D.G.;
RT "Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute
RT lymphoblastic leukemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:4917-4921(1995).
RN [8]
RP CHROMOSOMAL TRANSLOCATION WITH AML1.
RX PubMed=7780150;
RA Romana S.P., Mauchauffe M., le Coniat M., Chumakov I., le Paslier D.,
RA Berger R., Bernard O.A.;
RT "The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1
RT gene fusion.";
RL Blood 85:3662-3670(1995).
RN [9]
RP CHROMOSOMAL TRANSLOCATION WITH ACSL6.
RX PubMed=10502316;
RX DOI=10.1002/(SICI)1098-2264(199911)26:3<192::AID-GCC2>3.0.CO;2-E;
RA Yagasaki F., Jinnai I., Yoshida S., Yokoyama Y., Matsuda A.,
RA Kusumoto S., Kobayashi H., Terasaki H., Ohyashiki K., Asou N.,
RA Murohashi I., Bessho M., Hirashima K.;
RT "Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and
RT acute myelogenous leukemia with t(5;12)(q31;p13).";
RL Genes Chromosomes Cancer 26:192-202(1999).
RN [10]
RP CHROMOSOMAL TRANSLOCATION WITH CHIC2.
RX PubMed=10477709;
RA Cools J., Bilhou-Nabera C., Wlodarska I., Cabrol C., Talmant P.,
RA Bernard P., Hagemeijer A., Marynen P.;
RT "Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with
RT a t(4;12)(q11-q12;p13).";
RL Blood 94:1820-1824(1999).
RN [11]
RP PHOSPHORYLATION AT SER-22 AND SER-257, AND MUTAGENESIS OF SER-213;
RP SER-238 AND SER-257.
RX PubMed=12435397; DOI=10.1016/S0006-291X(02)02588-3;
RA Arai H., Maki K., Waga K., Sasaki K., Nakamura Y., Imai Y.,
RA Kurokawa M., Hirai H., Mitani K.;
RT "Functional regulation of TEL by p38-induced phosphorylation.";
RL Biochem. Biophys. Res. Commun. 299:116-125(2002).
RN [12]
RP CHROMOSOMAL TRANSLOCATION WITH MDS2.
RX PubMed=12203785; DOI=10.1002/gcc.10090;
RA Odero M.D., Vizmanos J.L., Roman J.P., Lahortiga I., Panizo C.,
RA Calasanz M.J., Zeleznik-Le N.J., Rowley J.D., Novo F.J.;
RT "A novel gene, MDS2, is fused to ETV6/TEL in a t(1;12)(p36.1;p13) in a
RT patient with myelodysplastic syndrome.";
RL Genes Chromosomes Cancer 35:11-19(2002).
RN [13]
RP CHROMOSOMAL TRANSLOCATION WITH PDGFRB.
RX PubMed=12181402; DOI=10.1056/NEJMoa020150;
RA Apperley J.F., Gardembas M., Melo J.V., Russell-Jones R., Bain B.J.,
RA Baxter E.J., Chase A., Chessells J.M., Colombat M., Dearden C.E.,
RA Dimitrijevic S., Mahon F.-X., Marin D., Nikolova Z., Olavarria E.,
RA Silberman S., Schultheis B., Cross N.C.P., Goldman J.M.;
RT "Response to imatinib mesylate in patients with chronic
RT myeloproliferative diseases with rearrangements of the platelet-
RT derived growth factor receptor beta.";
RL N. Engl. J. Med. 347:481-487(2002).
RN [14]
RP INTERACTION WITH L3MBTL1.
RX PubMed=12588862; DOI=10.1074/jbc.M300592200;
RA Boccuni P., MacGrogan D., Scandura J.M., Nimer S.D.;
RT "The human L(3)MBT Polycomb group protein is a transcriptional
RT repressor and interacts physically and functionally with TEL (ETV6).";
RL J. Biol. Chem. 278:15412-15420(2003).
RN [15]
RP INTERACTION WITH HDAC9.
RX PubMed=12590135; DOI=10.1074/jbc.M212935200;
RA Petrie K., Guidez F., Howell L., Healy L., Waxman S., Greaves M.,
RA Zelent A.;
RT "The histone deacetylase 9 gene encodes multiple protein isoforms.";
RL J. Biol. Chem. 278:16059-16072(2003).
RN [16]
RP INVOLVEMENT IN AML, VARIANT GLY-344 INS, AND CHARACTERIZATION OF
RP VARIANT GLY-344 INS.
RX PubMed=15806161; DOI=10.1038/sj.onc.1208588;
RA Barjesteh van Waalwijk van Doorn-Khosrovani S., Spensberger D.,
RA de Knegt Y., Tang M., Loewenberg B., Delwel R.;
RT "Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of
RT ETV6 protein in acute myeloid leukemia.";
RL Oncogene 24:4129-4137(2005).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-18 AND SER-22, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2; LYS-11 AND LYS-302, MASS
RP SPECTROMETRY, AND CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-22 AND SER-213, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [23]
RP STRUCTURE BY NMR OF 338-442.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of ets domain transcriptional factor ETV6
RT protein.";
RL Submitted (DEC-2006) to the PDB data bank.
CC -!- FUNCTION: Transcriptional repressor; binds to the DNA sequence 5'-
CC CCGGAAGT-3'.
CC -!- SUBUNIT: Can form homodimers or heterodimers with TEL2 or FLI1.
CC Interacts with L3MBTL1 and HDAC9.
CC -!- INTERACTION:
CC Q9UKV0-3:HDAC9; NbExp=3; IntAct=EBI-1372759, EBI-765476;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- PTM: Phosphorylation of Ser-257 by MAPK14 (p38) inhibits ETV6
CC transcriptional repression.
CC -!- DISEASE: Note=A chromosomal aberration involving ETV6 is found in
CC a form of chronic myelomonocytic leukemia (CMML). Translocation
CC t(5;12)(q33;p13) with PDGFRB. It is characterized by abnormal
CC clonal myeloid proliferation and by progression to acute
CC myelogenous leukemia (AML).
CC -!- DISEASE: Note=Chromosomal aberrations involving ETV6 are found in
CC a form of acute myeloid leukemia (AML). Translocation
CC t(12;22)(p13;q11) with MN1; translocation t(4;12)(q12;p13) with
CC CHIC2.
CC -!- DISEASE: Note=Chromosomal aberrations involving ETV6 are found in
CC childhood acute lymphoblastic leukemia (ALL). Translocations
CC t(12;21)(p12;q22) and t(12;21)(p13;q22) with RUNX1/AML1.
CC -!- DISEASE: Note=A chromosomal aberration involving ETV6 is found in
CC a form of pre-B acute myeloid leukemia. Translocation
CC t(9;12)(p24;p13) with JAK2.
CC -!- DISEASE: Note=A chromosomal aberration involving ETV6 is found in
CC myelodysplastic syndrome (MDS) with basophilia. Translocation
CC t(5;12)(q31;p13) with ACSL6.
CC -!- DISEASE: Note=A chromosomal aberration involving ETV6 is found in
CC acute eosinophilic leukemia (AEL). Translocation t(5;12)(q31;p13)
CC with ACSL6.
CC -!- DISEASE: Note=A chromosomal aberration involving ETV6 is found in
CC myelodysplastic syndrome (MDS). Translocation t(1;12)(p36.1;p13)
CC with MDS2.
CC -!- DISEASE: Myeloproliferative disorder chronic with eosinophilia
CC (MPE) [MIM:131440]: A hematologic disorder characterized by
CC malignant eosinophils proliferation. Note=The gene represented in
CC this entry is involved in disease pathogenesis. A chromosomal
CC aberration involving ETV6 is found in many instances of
CC myeloproliferative disorder chronic with eosinophilia.
CC Translocation t(5;12) with PDGFRB on chromosome 5 creating an
CC ETV6-PDGFRB fusion protein.
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 gene represented in
CC this entry is involved in disease pathogenesis.
CC -!- DISEASE: Note=A chromosomal aberration involving ETV6 is found in
CC acute lymphoblastic leukemia. Translocation t(9;12)(p13;p13) with
CC PAX5.
CC -!- SIMILARITY: Belongs to the ETS family.
CC -!- SIMILARITY: Contains 1 ETS DNA-binding domain.
CC -!- SIMILARITY: Contains 1 PNT (pointed) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=ABI30005.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ETV6ID38.html";
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DR EMBL; U11732; AAA19786.1; -; mRNA.
DR EMBL; AK289441; BAF82130.1; -; mRNA.
DR EMBL; CH471094; EAW96240.1; -; Genomic_DNA.
DR EMBL; BC043399; AAH43399.1; -; mRNA.
DR EMBL; U61375; AAC50690.1; -; Genomic_DNA.
DR EMBL; U63312; AAB17134.1; -; Genomic_DNA.
DR EMBL; U63313; AAB17135.1; -; Genomic_DNA.
DR EMBL; DQ841178; ABI30005.1; ALT_INIT; mRNA.
DR RefSeq; NP_001978.1; NM_001987.4.
DR UniGene; Hs.504765; -.
DR PDB; 1JI7; X-ray; 1.45 A; A/B/C=47-123.
DR PDB; 1LKY; X-ray; 2.30 A; A/B/C/D/E/F=47-123.
DR PDB; 2DAO; NMR; -; A=338-442.
DR PDB; 2QAR; X-ray; 2.40 A; A/B/D/E=47-124.
DR PDB; 2QB0; X-ray; 2.56 A; A/C=47-123.
DR PDB; 2QB1; X-ray; 2.61 A; A/B=47-121.
DR PDBsum; 1JI7; -.
DR PDBsum; 1LKY; -.
DR PDBsum; 2DAO; -.
DR PDBsum; 2QAR; -.
DR PDBsum; 2QB0; -.
DR PDBsum; 2QB1; -.
DR ProteinModelPortal; P41212; -.
DR SMR; P41212; 47-124, 338-442.
DR DIP; DIP-17028N; -.
DR IntAct; P41212; 7.
DR MINT; MINT-7944472; -.
DR STRING; 9606.ENSP00000266427; -.
DR PhosphoSite; P41212; -.
DR DMDM; 730927; -.
DR PaxDb; P41212; -.
DR PeptideAtlas; P41212; -.
DR PRIDE; P41212; -.
DR DNASU; 2120; -.
DR Ensembl; ENST00000396373; ENSP00000379658; ENSG00000139083.
DR GeneID; 2120; -.
DR KEGG; hsa:2120; -.
DR UCSC; uc001qzz.3; human.
DR CTD; 2120; -.
DR GeneCards; GC12P011802; -.
DR HGNC; HGNC:3495; ETV6.
DR HPA; HPA000264; -.
DR MIM; 131440; phenotype.
DR MIM; 600618; gene.
DR MIM; 601626; phenotype.
DR neXtProt; NX_P41212; -.
DR Orphanet; 98823; Chronic myelomonocytic leukemia.
DR Orphanet; 2665; Congenital mesoblastic nephroma.
DR Orphanet; 2030; Fibrosarcoma.
DR Orphanet; 99860; Precursor B-cell acute lymphoblastic leukemia.
DR PharmGKB; PA27909; -.
DR eggNOG; NOG270606; -.
DR HOGENOM; HOG000012982; -.
DR HOVERGEN; HBG005617; -.
DR InParanoid; P41212; -.
DR KO; K03211; -.
DR OMA; HQEPYPL; -.
DR OrthoDB; EOG7R2BJB; -.
DR PhylomeDB; P41212; -.
DR ChiTaRS; ETV6; human.
DR EvolutionaryTrace; P41212; -.
DR GeneWiki; ETV6; -.
DR GenomeRNAi; 2120; -.
DR NextBio; 8571; -.
DR PRO; PR:P41212; -.
DR ArrayExpress; P41212; -.
DR Bgee; P41212; -.
DR CleanEx; HS_ETV6; -.
DR Genevestigator; P41212; -.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:InterPro.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0030154; P:cell differentiation; IEA:Ensembl.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 1.10.150.50; -; 1.
DR InterPro; IPR000418; Ets_dom.
DR InterPro; IPR003118; Pointed_dom.
DR InterPro; IPR013761; SAM/pointed.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00178; Ets; 1.
DR Pfam; PF02198; SAM_PNT; 1.
DR PRINTS; PR00454; ETSDOMAIN.
DR SMART; SM00413; ETS; 1.
DR SMART; SM00251; SAM_PNT; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR PROSITE; PS00345; ETS_DOMAIN_1; FALSE_NEG.
DR PROSITE; PS00346; ETS_DOMAIN_2; 1.
DR PROSITE; PS50061; ETS_DOMAIN_3; 1.
DR PROSITE; PS51433; PNT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Chromosomal rearrangement;
KW Complete proteome; Disease mutation; DNA-binding; Nucleus;
KW Phosphoprotein; Proto-oncogene; Reference proteome; Repressor;
KW Transcription; Transcription regulation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 452 Transcription factor ETV6.
FT /FTId=PRO_0000204121.
FT DOMAIN 40 124 PNT.
FT DNA_BIND 339 420 ETS.
FT SITE 11 12 Breakpoint for translocation to form
FT CHIC2-ETV6 in AML.
FT SITE 54 55 Breakpoint for translocation to form
FT ETV6-MDS2 in MDS.
FT SITE 55 56 Breakpoint for translocation to form
FT PAX5-ETV6.
FT SITE 336 337 Breakpoint for translocation to form
FT ETV6-AML1 in ALL.
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 11 11 N6-acetyllysine.
FT MOD_RES 18 18 Phosphothreonine.
FT MOD_RES 22 22 Phosphoserine.
FT MOD_RES 213 213 Phosphoserine.
FT MOD_RES 257 257 Phosphoserine; by MAPK14.
FT MOD_RES 302 302 N6-acetyllysine.
FT VARIANT 344 344 Y -> YG (in one individual with AML;
FT somatic mutation; unable to repress
FT transcription).
FT /FTId=VAR_034600.
FT MUTAGEN 22 22 S->A: No effect.
FT MUTAGEN 213 213 S->A: No effect.
FT MUTAGEN 238 238 S->A: No effect.
FT MUTAGEN 257 257 S->A: No phosphorylation by MAPK14.
FT HELIX 52 54
FT HELIX 58 60
FT HELIX 63 76
FT TURN 84 87
FT HELIX 91 94
FT HELIX 99 105
FT TURN 107 109
FT HELIX 110 122
FT HELIX 341 350
FT HELIX 352 354
FT TURN 355 357
FT STRAND 358 362
FT HELIX 363 365
FT STRAND 367 371
FT HELIX 373 383
FT HELIX 391 403
FT STRAND 406 408
FT STRAND 411 419
FT HELIX 424 426
FT STRAND 430 432
FT HELIX 434 438
SQ SEQUENCE 452 AA; 53000 MW; DEC45682ECADECBB CRC64;
MSETPAQCSI KQERISYTPP ESPVPSYASS TPLHVPVPRA LRMEEDSIRL PAHLRLQPIY
WSRDDVAQWL KWAENEFSLR PIDSNTFEMN GKALLLLTKE DFRYRSPHSG DVLYELLQHI
LKQRKPRILF SPFFHPGNSI HTQPEVILHQ NHEEDNCVQR TPRPSVDNVH HNPPTIELLH
RSRSPITTNH RPSPDPEQRP LRSPLDNMIR RLSPAERAQG PRPHQENNHQ ESYPLSVSPM
ENNHCPASSE SHPKPSSPRQ ESTRVIQLMP SPIMHPLILN PRHSVDFKQS RLSEDGLHRE
GKPINLSHRE DLAYMNHIMV SVSPPEEHAM PIGRIADCRL LWDYVYQLLS DSRYENFIRW
EDKESKIFRI VDPNGLARLW GNHKNRTNMT YEKMSRALRH YYKLNIIRKE PGQRLLFRFM
KTPDEIMSGR TDRLEHLESQ ELDEQIYQED EC
//

MIM 131440
*RECORD*
*FIELD* NO
131440
*FIELD* TI
#131440 MYELOPROLIFERATIVE DISORDER, CHRONIC, WITH EOSINOPHILIA
;;MPE; EMP;;
EOSINOPHILS, MALIGNANT PROLIFERATION OF
read more*FIELD* TX
A number sign (#) is used with this entry because in many instances the
disorder is caused by a translocation between chromosomes 12 and 5,
creating an ETV6 (600618)-PDGFRB (173410) fusion gene.

Keene et al. (1987) suggested a causal relationship between abnormality
of the 12p13 band and malignant eosinophil proliferation; 2 of the 4
patients in their report had translocations involving chromosome 5q3.
Golub et al. (1994) showed that the previously described t(5;12)
translocation, characteristic of some cases of chronic myelomonocytic
leukemia, was associated with a fusion gene linking ETV6 with
platelet-derived growth factor receptor-beta (PDGFRB), which maps to
5q31-q32. A considerable number of cases of chronic myeloproliferative
disorder associated with a t(5;12) translocation have been reported, and
the PDGFRB gene is known to be rearranged in some of these cases. There
are additional cases involving translocations of the PDGFRB-containing
region of chromosome 5 and chromosome partners other than 12p13, e.g.,
chromosome 14 (see 604505). Although heterogeneous, all these leukemias
have some common features, most notably the frequent presence of
eosinophilia in peripheral blood and bone marrow.

Apperley et al. (2002) reported treatment of 4 patients who had chronic
myeloproliferative disorders and chromosome translocations involving
5q33. Three of the 4 patients presented with leukocytosis and
eosinophilia; their leukemia cells carried the ETV6/PDGFRB fusion gene.
The fourth patient had leukocytosis, eosinophilia, and a t(5;12)
translocation involving PDGFRB on chromosome 5 and an unknown partner
gene; he also had extensive raised, ulcerated skin lesions that had been
present for a long time. All 4 patients responded to treatment with
imatinib mesylate, an inhibitor of the kinase activity of PDGFRB and
other protein tyrosine kinases.

*FIELD* RF
1. Apperley, J. F.; Gardembas, M.; Melo, J. V.; Russell-Jones, R.;
Bain, B. J.; Baxter, E. J.; Chase, A.; Chessells, J. M.; Colombat,
M.; Dearden, C. E.; Dimitrijevic, S.; Mahon, F.-X.; Marin, D.; Nikolova,
Z.; Olavarria, E.; Silberman, S.; Schultheis, B.; Cross, N. C. P.;
Goldman, J. M.: Response to imatinib mesylate in patients with chronic
myeloproliferative diseases with rearrangements of the platelet-derived
growth factor receptor beta. New Eng. J. Med. 347: 481-487, 2002.

2. Golub, T. R.; Barker, G. F.; Lovett, M.; Gilliland, D. G.: Fusion
of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic
leukemia with t(5;12) chromosomal translocation. Cell 77: 307-316,
1994.

3. Keene, P.; Mendelow, B.; Pinto, M. R.; Bezwoda, W.; MacDougall,
L.; Falkson, G.; Ruff, P.; Bernstein, R.: Abnormalities of chromosome
12p13 and malignant proliferation of eosinophils: a nonrandom association. Brit.
J. Haemat. 67: 25-31, 1987.

*FIELD* CS

Oncology:
Malignant eosinophil proliferation

Inheritance:
Autosomal dominant (12p13)

*FIELD* CN
Victor A. McKusick - updated: 9/16/2002

*FIELD* CD
Victor A. McKusick: 11/8/1988

*FIELD* ED
tkritzer: 09/25/2002
tkritzer: 9/25/2002
alopez: 9/18/2002
tkritzer: 9/16/2002
mark: 2/11/1998
mimadm: 9/24/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 3/17/1989
root: 11/18/1988

MIM 600618
*RECORD*
*FIELD* NO
600618
*FIELD* TI
*600618 ETS VARIANT GENE 6; ETV6
;;TRANSLOCATION, ETS, LEUKEMIA; TEL;;
TEL1 ONCOGENE
read moreETV6/PDGFRB FUSION GENE, INCLUDED;;
ETV6/MN1 FUSION GENE, INCLUDED;;
ETV6/AML1 FUSION GENE, INCLUDED;;
ETV6/ARNT FUSION GENE, INCLUDED;;
ETV6/MDS2 FUSION GENE, INCLUDED;;
ETV6/ABL2 FUSION GENE, INCLUDED;;
ETV6/PER1 FUSION GENE, INCLUDED;;
ETV6/NTRK3 FUSION GENE, INCLUDED;;
ETV6/ACS2 FUSION GENE, INCLUDED;;
ETV6/BTL FUSION GENE, INCLUDED;;
ETV6/JAK2 FUSION GENE, INCLUDED;;
ETV6/RUNX1 FUSION GENE, INCLUDED
*FIELD* TX

DESCRIPTION

The ETV6 gene encodes an Ets family transcription factor and is
frequently rearranged or fused with other genes in human leukemias of
myeloid or lymphoid origins (Wang et al., 1997).

CLONING

Golub et al. (1994) identified the ETV6 gene as part of a fusion
transcript resulting from a somatic t(5;12)(q33;p13) translocation in
chronic myelomonocytic leukemia (see 607785) cancer cells. The
translocation was found to consist of a novel gene on chromosome 12p13
and the PDGFRB (173410) gene on 5q33. Golub et al. (1994) isolated
clones corresponding to the coding sequence from a chromosome 12 cDNA
library. Portions of the gene showed homology to the ETS family of
transcription factors, and it was designated 'TEL' for translocation,
ETS, leukemia. Northern blot analysis detected 3 transcripts of 6.5 kb,
4.5 kb, and 2.4 kb in all tissues examined.

Baens et al. (1996) developed contigs containing the complete coding
sequence and the 5-prime and 3-prime UTRs of the ETV6 gene. The
helix-loop-helix (HLH) motif is coded by exons 3 and 4, whereas exons 6
to 8 encode for the ETS DNA-binding domain. The ETV6 gene is flanked at
its 5-prime and 3-prime ends by markers D12S1697 and D12S98,
respectively.

GENE STRUCTURE

Baens et al. (1996) determined that the ETV6 gene contains 8 exons
spanning 240 kb. They identified an alternative exon 1B located within
intron 2.

MAPPING

Stegmaier et al. (1995) mapped the ETV6 gene to chromosome 12p13.

GENE FUNCTION

Stegmaier et al. (1995) presented evidence that the TEL gene may act as
a tumor suppressor gene. They noted noted that 5% of children with acute
lymphocytic leukemia (ALL) have 12p13-p12 deletions. Using markers
flanking the TEL gene, Stegmaier et al. (1995) found that 15% of 81
informative children with ALL had TEL loss of heterozygosity that was
not evident on cytogenetic analysis. Detailed examination showed that
the critically deleted region included 2 candidate suppressor genes: TEL
and KIP (600778), the gene encoding the cyclin-dependent kinase
inhibitor p27.

- ETV6/PDGFRB Fusion Gene

In bone marrow cells from a 17-year-old male with chronic myelomonocytic
leukemia, Golub et al. (1994) identified a somatic t(5;12)(q33;p13)
translocation consisting of the 154 N terminal residues of ETV6 linked
to the transmembrane and tyrosine kinase domains of the PDGFRB on
chromosome 5q33. The entire ligand-binding domain of PDGFRB and the
putative DNA-binding domain of ETV6 were both excluded from the fusion
transcript. This same rearrangement was detected in 3 additional
patients with chronic myelomonocytic leukemia. The index patient
subsequently developed acute myelogenous leukemia (AML; 601626)
associated with other genetic alterations, suggesting that the
t(5;12)(q33;p13) translocation was an early step in a multistep
progression to full AML.

Apperley et al. (2002) reported successful response to therapy with the
tyrosine kinase inhibitor imatinib mesylate in 3 patients with chronic
myeloproliferative disorder (131440) and a t(5;12) translocation. The
patients' leukemic cells carried the ETV6/PDGFRB fusion gene.

Pierce et al. (2008) showed that expression of TEL/PDGFRB in murine
myeloid FDCP-Mix cells prevented cell differentiation, increased cell
survival, increased the level of phosphatidylinositol
3,4,5-trisphosphate (PtdInsP3), and increased the expression and
phosphorylation of Thoc5 (612733). Elevated Thoc5 expression also led to
increased cell survival and PtdInsP3 levels, suggesting that the effects
associated with TEL/PDGFRB expression were due, at least in part, to
Thoc5 upregulation.

- ETV6/AML1 Fusion Gene

Golub et al. (1995) documented fusion of TEL to the AML1 gene (151385)
on chromosome 21 in 2 pediatric patients with acute lymphocytic leukemia
with t(12;21) translocations. The findings implicated TEL in the
pathogenesis of leukemia through its fusion to either a receptor
tyrosine kinase, such as PDGFRB, or a transcription factor, such as
AML1.

Using RT-PCR, Romana et al. (1995) identified the TEL/AML1 fusion gene
in 8 (16%) of 46 childhood B-cell lymphoblastic leukemia cells, only 1
of which showed a 12p abnormality by classic cytogenetic techniques. The
authors concluded that t(12;21) is the most frequent translocation in
childhood B-lineage ALL.

Ford et al. (1998) reported the extraordinary case of monozygotic twins
in whom common acute lymphoblastic leukemia was diagnosed at ages 3.5
years and 4 years. The twins' leukemic DNA shared the same unique (or
clonotypic) but nonconstitutive TEL/AML1 fusion sequence. The most
plausible explanation for this finding was thought to be a single cell
origin of the TEL/AML fusion in 1 fetus in utero, probably as a
leukemia-initiating mutation, followed by intraplacental metastasis of
clonal progeny to the other twin. Clonal identity was further supported
by the finding that the leukemic cells in the twins shared an identical
rearranged IGH allele. These data had implications for the etiology and
natural history of childhood leukemia.

- ETV6/MN1 Fusion Gene

Buijs et al. (1995) showed that the MN1 gene (156100) on 22q11 is fused
to the TEL gene in the t(12;22)(p13;q11) translocation that is observed
in different myeloid malignancies.

- 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 at 12p13 and the JAK2 gene (147796) 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.

- ETV6/NTRK3 Fusion Gene

Knezevich et al. (1998) detected a recurrent t(12;15)(p13;q25)
translocation consisting of fusion of the ETV6 gene with the NTRK3 gene
(191316) on 15q25 in 3 congenital fibrosarcomas analyzed. Congenital (or
infantile) fibrosarcoma (CFS) is a malignant tumor of fibroblasts that
occurs in patients aged 2 or younger. CFS is unique among human sarcomas
in that it has an excellent prognosis and very low metastatic rate. CFS
is histologically identical to adult-type fibrosarcoma (ATFS); however,
ATFS is an aggressive malignancy of adults and older children that has a
poor prognosis. The same translocation was not identified in ATFS or
infantile fibromatosis (228550), a histologically similar but benign
fibroblastic proliferation occurring in the same age group as CFS.
ETV6/NTRK3 fusion transcripts encoded the HLH protein dimerization
domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of
NTRK3. Presumably, the chimeric protein tyrosine kinase contributed to
oncogenesis by dysregulation of NTRK3 signal transduction pathways.

- ETV6/ACS2 Fusion Gene

Yagasaki et al. (1999) identified a recurrent t(5;12)(q31;p13)
translocation, resulting in an ETV6/ACS2 (604443) fusion gene in a
patient with refractory anemia with excess blasts with basophilia, a
patient with AML with eosinophilia, and a patient with acute
eosinophilic leukemia (AEL). The ETV6/ACS2 fusion transcripts showed an
out-frame fusion of exon 1 of ETV6 to exon 1 of ACS2 in the patient with
AEL, an out-frame fusion of exon 1 of ETV6 to exon 11 of ACS2 in the
patient with AML, and a short in-frame fusion of exon 1 of ETV6 to the
3-prime untranslated region of ACS2 in the patient with refractory
anemia. Reciprocal ACS2/ETV6 transcripts were identified in 2 of the
cases. FISH with ETV6 cosmids on 12p13, and BACs and PIs on 5q31,
demonstrated that the 5q31 breakpoints of the AML and AEL cases involved
the 5-prime portion of the ACS2 gene, and that the 5q31 breakpoint of
the refractory anemia case involved the 3-prime portion of the ACS2
gene. None of the resulting chimeric transcripts except for the
ACS2/ETV6 transcript in the refractory anemia case led to a fusion
protein.

- ETV6/ABL2 Fusion Gene

Cazzaniga et al. (1999) identified a t(1;12)(q25;p13) translocation
involving the ETV6 gene and the ABL2 (164690) gene in a patient with
acute myeloid leukemia M4 with eosinophilia. The novel transcript
resulted in a chimeric protein consisting of the helix-loop-helix
oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine
kinase domains of ABL2. The reciprocal transcript ABL2/ETV6 was also
detected in the patient's RNA by RT-PCR, although at a lower expression
level.

- ETV6/BTL Fusion Gene

Cools et al. (1999) reported 4 cases of acute myeloid leukemia with very
immature myeloblasts and a t(4;12)(q11-q12;p13) translocation in which
ETV6 was linked with the BTL gene (604332). RT-PCR experiments indicated
that expression of the BTL/ETV6 transcript, but not of the reciprocal
ETV6/BTL transcript, was a common finding in these leukemias. In
contrast to most of the other ETV6 fusions, both the complete
helix-loop-helix and ETS DNA-binding domains of ETV6 were present in the
predicted BTL/ETV6 fusion protein, and a chimeric gene was transcribed
from the BTL promoter.

- ETV6/ARNT Fusion Gene

Salomon-Nguyen et al. (2000) determined that a t(1;12)(q21;p13)
translocation observed in a case of acute myeloblastic leukemia (AML-M2)
resulted in a fusion protein containing the amino-terminal of TEL and
essentially all of the ARNT gene (126110). The involvement of ARNT in
human leukemogenesis had not previously been described.

- ETV6/MDS2 Fusion Gene

Odero et al. (2002) identified a t(1;12)(p36.1;p13) translocation in an
MDS patient that resulted in the fusion of exons 1 and 2 of ETV6 to
exons 6 and 7 of MDS2 (607305). The predicted protein is out of frame
and contains the first 54 amino acids of ETV6 followed by 4 novel amino
acids from the MDS2 sequence. The truncated ETV6 protein lacks critical
functional domains.

- ETV6/PER1 Fusion Gene

Penas et al. (2003) cloned a novel cryptic translocation,
t(12;17)(p13;p12-p13), occurring in a patient with acute myeloid
leukemia evolving from a chronic myelomonocytic leukemia. They
identified a fusion transcript between exon 1 of the ETV6 gene and the
antisense strand of PER1 (602260). The ETV6/PER1 fusion transcript did
not produce a fusion protein, and no other fusion transcripts could be
detected. Penas et al. (2003) hypothesized that in the absence of a
fusion protein, the inactivation of PER1 or deregulation of a gene in
the neighborhood of PER1 may contribute to the pathogenesis of leukemia
with this translocation.

- ETV6/RUNX1 Fusion Gene

Anderson et al. (2011) examined the genetic architecture of cancer at
the subclonal and single-cell level and in cells responsible for cancer
clone maintenance and propagation in childhood acute lymphoblastic
leukemia (see 613065) in which the ETV6/RUNX1 (151385) gene fusion is an
early or initiating genetic lesion followed by a modest number of
recurrent or driver copy number alterations. By multiplexing
fluorescence in situ hybridization probes for these mutations, up to 8
genetic abnormalities could be detected in single cells, a genetic
signature of subclones identified, and a composite picture of subclonal
architecture and putative ancestral trees assembled. Anderson et al.
(2011) observed that subclones in acute lymphoblastic leukemia have
variegated genetics and complex nonlinear or branching evolutionary
histories. Copy number alterations are independently and reiteratively
acquired in subclones of individual patients, and in no preferential
order. Clonal architecture is dynamic and is subject to change in the
lead-up to a diagnosis and in relapse. Leukemia-propagating cells,
assayed by serial transplantation in nonobese diabetic/severe combined
immunodeficiency (NOD/SCID) IL2R-gamma (308380)-null mice, are also
genetically variegated, mirroring subclonal patterns, and vary in
competitive regenerative capacity in vivo.

CYTOGENETICS

Cytogenetic abnormalities involving the short arm of chromosome 12 have
been documented in a wide variety of hematopoietic malignancies,
including acute lymphoblastic leukemia (ALL), acute myeloblastic
leukemia, and myelodysplastic syndromes. Among 20 patients with 12q
deletions or translocations, Kobayashi et al. (1994) showed that most
changes were clustered within a 1.39-Mb region, suggesting that a single
gene on 12p13 was affected in these leukemias.

Raynaud et al. (1996) reported 5 patients with an identical reciprocal
translocation between 3q26 and 12p13. This nonrandom cytogenetic change
was observed in 4 patients with myelodysplastic syndrome rapidly
progressing to acute myeloid leukemia and was found at blast crisis of 1
patient with Philadelphia chromosome-positive CML. The abnormality was
associated with a very poor prognosis. Fluorescence in situ
hybridization with 3q26 and 12p13 probes was performed on metaphases
from these 5 patients. The results were consistent with scattering of
the breakpoints previously described in 3q26 rearrangements. Breakpoints
at 12p13 involved the ETV6 gene in 3 myelodysplastic syndrome cases.

Berger et al. (1997) described 3 novel translocations involving the
TEL/ETV6 gene on chromosome 12: t(X;12)(q28;p13), t(1;12)(q21;p13), and
t(9;12)(p23-24;p13).

Cave et al. (1997) demonstrated that ETV6 is a target of chromosome 12p
deletions in t(12;21) childhood acute lymphocytic leukemia.

Odero et al. (2001) stated that 35 different chromosome bands had been
involved in ETV6 translocations, of which 13 had been cloned. Adding
further data, they concluded that ETV6 is involved in 41 translocations.

MOLECULAR GENETICS

Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2005) analyzed 300
patients newly diagnosed with acute myeloid leukemia (AML; 601626) for
mutations in the coding region of the ETV6 gene and identified 5 somatic
heterozygous mutations affecting either the homodimerization or the
DNA-binding domain (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.

HISTORY

- ETV6/ABL1 Fusion Gene

Papadopoulos et al. (1995) identified a case of ALL with a previously
undescribed fusion between the TEL gene and the ABL gene (189980) on
chromosome 9q. The fusion protein showed elevated tyrosine kinase
activity. However, Janssen et al. (1995) did not identify any TEL/ABL
fusion products using RT-PCR to screen 186 adult ALL and 30 childhood
ALL patients. Nilsson et al. (1998) also found no instance of ETV6/ABL
fusion. in a study of a group of 67 cases of chronic myeloid disorders.

ANIMAL MODEL

By gene targeting in mice, Wang et al. (1997) showed that TEL function
is required for viability of the developing mouse. The TEL -/- mice
suffered a yolk sac angiogenic defect; TEL also appeared essential for
the survival of selected neural and mesenchymal populations within the
embryo proper. Wang et al. (1998) generated mouse chimeras with TEL -/-
embryonic stem cells to examine a possible requirement in adult
hematopoiesis. They found that although TEL function is not required for
the intrinsic proliferation and/or differentiation of adult-type
hematopoietic lineages in the yolk sac and fetal liver, it is essential
for the establishment of hematopoiesis of all lineages in the bone
marrow. These findings established TEL as the first transcription factor
required specifically for hematopoiesis within the bone marrow, as
opposed to other sites of hematopoietic activity during development.

STAT5 (see STAT5A, 601511; STAT5B, 604260) 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/JAK2 (147796) 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.

Montpetit and Sinnett (2001) reported a comparative analysis of the ETV6
gene in vertebrate genomes. They cloned the homolog of ETV6 from the
compact genome of the pufferfish Fugu rubripes. In that organism the
gene, composed of 8 exons, spans about 15 kb and is 16 times smaller
than its human counterpart, mainly because of reduced intron size. Three
of the 7 introns were unusually large (more than 2 kb). As expected, the
PNT and ETS domains were highly conserved from Fugu to human. There were
also conserved putative regulatory elements in the promoter as well as
in the large intron 2 of Fugu ETV6.

Creation of the TEL/AML1 fusion disrupts 1 copy of the TEL gene and 1
copy of the AML1 gene; loss of 1 or the other is associated with cases
of acute leukemia without the presence of the TEL/AML1 fusion gene. To
determine if TEL/AML1 can contribute to leukemogenesis, Bernardin et al.
(2002) transduced marrow from C57BL/6 mice with a retroviral vector
expressing TEL/AML1 or with a control vector. Two of the 9 TEL/AML1 mice
developed ALL, whereas none of the 20 control mice developed leukemia.
Bernardin et al. (2002) also used the TEL/AML1 vector to transduce
marrow from C57BL/6 mice lacking the overlapping p16(INK4a)p19(ARF)
genes (600160) and transplanted the cells into wildtype recipients. No
control mice died, but 6 of 8 TEL/AML1/p16p19 mice died with leukemia.
These findings indicated that TEL/AML1 contributes to leukemogenesis and
may cooperate with loss of p16p19 to transform lymphoid progenitors.

Tsuzuki et al. (2004) analyzed hemopoiesis in mice syngeneically
transplanted with TEL/AML1-transduced bone marrow stem cells. TEL/AML1
expression was associated with an accumulation/expansion of primitive
Kit (164920)-positive multipotent progenitors and a modest increase in
myeloid colony-forming cells. TEL/AML1 expression was, however,
permissive for myeloid differentiation. Analysis of B lymphopoiesis
revealed an increase in early pro-B cells but a differentiation deficit
beyond that stage, which resulted in lower B-cell production in the
marrow. TEL/AML1-positive B-cell progenitors exhibited reduced
expression of genes crucial for the pro-B to pre-B cell transition.

*FIELD* AV
.0001
LEUKEMIA, ACUTE MYELOID, SOMATIC
ETV6, GLU76TER

In leukemic blast cells of a patient with acute myeloid leukemia
(601626), Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2005)
identified a somatic heterozygous 500G-T transversion in the ETV6 gene,
resulting in a glu76-to-ter (E76X) substitution in the N-terminal
pointed (PNT) homodimerization domain. The mutant protein was unable to
repress transcription and showed dominant-negative effects. The mutation
was not found in nonhematopoietic tissue from this patient.

.0002
LEUKEMIA, ACUTE MYELOID, SOMATIC
ETV6, 3-BP INS, 1307GGG

In leukemic blast cells of a patient with acute myeloid leukemia
(601626), Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2005)
identified a somatic heterozygous 3-bp insertion (1307insGGG) in the
ETV6 gene, resulting in the insertion of a glycine between codons 344
and 345 in the DNA binding domain. The mutant protein was unable to
repress transcription and showed dominant-negative effects.

*FIELD* RF
1. Anderson, K.; Lutz, C.; van Delft, F. W.; Bateman, C. M.; Guo,
Y.; Colman, S. M.; Kempski, H.; Moorman, A. V.; Titley, I.; Swansbury,
J.; Kearney, L.; Enver, T.; Greaves, M.: Genetic variegation of clonal
architecture and propagating cells in leukaemia. Nature 469: 356-361,
2011.

2. Apperley, J. F.; Gardembas, M.; Melo, J. V.; Russell-Jones, R.;
Bain, B. J.; Baxter, E. J.; Chase, A.; Chessells, J. M.; Colombat,
M.; Dearden, C. E.; Dimitrijevic, S.; Mahon, F.-X.; Marin, D.; Nikolova,
Z.; Olavarria, E.; Silberman, S.; Schultheis, B.; Cross, N. C. P.;
Goldman, J. M.: Response to imatinib mesylate in patients with chronic
myeloproliferative diseases with rearrangements of the platelet-derived
growth factor receptor beta. New Eng. J. Med. 347: 481-487, 2002.

3. Baens, M.; Peeters, P.; Guo, C.; Aerssens, J.; Marynen, P.: Genomic
organization of TEL: the human ETS-variant gene 6. Genome Res. 6:
404-413, 1996.

4. Barjesteh van Waalwijk van Doorn-Khosrovani, S.; Spensberger, D.;
de Knegt, Y.; Tang, M.; Lowenberg, B.; Delwel, R.: Somatic heterozygous
mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute
myeloid leukemia. Oncogene 24: 4129-4137, 2005.

5. Berger, R.; Le Coniat, M.; Lacronique, V.; Daniel, M.-T.; Lessard,
M.; Berthou, C.; Marynen, P.; Bernard, O.: Chromosome abnormalities
of the short arm of chromosome 12 in hematopoietic malignancies: a
report including three novel translocations involving the TEL/ETV6
gene. Leukemia 11: 1400-1403, 1997.

6. Bernardin, F.; Yang, Y.; Cleaves, R.; Zahurak, M.; Cheng, L.; Civin,
C. I.; Friedman, A. D.: TEL-AML1, expressed from t(12;21) in human
acute lymphocytic leukemia, induces acute leukemia in mice. Cancer
Res. 62: 3904-3908, 2002.

7. Buijs, A.; Sherr, S.; van Baal, S.; van Bezouw, S.; van der Plas,
D.; Geurts van Kessel, A.; Riegman, P.; Lekanne Deprez, R.; Zwarthoff,
E.; Hagemeijer, A.; Grosveld, G.: Translocation (12;22)(p13;q11)
in myeloproliferative disorders results in fusion of the ETS-like
TEL gene on 12q13 to the MN1 gene on 22q11. Oncogene 10: 1511-1519,
1995. Note: Erratum: Oncogene 11: 809 only, 1995.

8. Cave, H.; Cacheux, V.; Raynaud, S.; Brunie, G.; Bakkus, M.; Cochaux,
P.; Preudhomme, C.; Lai, J. L.; Vilmer, E.; Grandchamp, B.: ETV6
is the target of chromosome 12p deletions in t(12;21) childhood acute
lymphocytic leukemia. Leukemia 11: 1459-1464, 1997.

9. Cazzaniga, G.; Tosi, S.; Aloisi, A.; Giudici, G.; Daniotti, M.;
Pioltelli, P.; Kearney, L.; Biondi, A.: The tyrosine kinase Abl-related
gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13):
molecular cloning of both reciprocal transcripts. Blood 94: 4370-4373,
1999.

10. Cools, J.; Bilhou-Nabera, C.; Wlodarska, I.; Cabrol, C.; Talmant,
P.; Bernard, P.; Hagemeijer, A.; Marynen, P.: Fusion of a novel gene,
BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13). Blood 94:
1820-1824, 1999.

11. Ford, A. M.; Bennett, C. A.; Price, C. M.; Bruin, M. C. A.; Van
Wering, E. R.; Greaves, M.: Fetal origins of the TEL-AML1 fusion
gene in identical twins with leukemia. Proc. Nat. Acad. Sci. 95:
4584-4588, 1998.

12. Golub, T. R.; Barker, G. F.; Bohlander, S. K.; Hiebert, S. W.;
Ward, D. C.; Bray-Ward, P.; Morgan, E.; Raimondi, S. C.; Rowley, J.
D.; Gilliland, D. G.: Fusion of the TEL gene on 12p13 to the AML1
gene on 21q22 in acute lymphoblastic leukemia. Proc. Nat. Acad. Sci. 92:
4917-4921, 1995.

13. Golub, T. R.; Barker, G. F.; Lovett, M.; Gilliland, D. G.: Fusion
of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic
leukemia with t(5;12) chromosomal translocation. Cell 77: 307-316,
1994.

14. Janssen, J. W. G.; Ridge, S. A.; Papadopoulos, P.; Cotter, F.;
Ludwig, W.-D.; Fonatsch, C.; Rieder, H.; Ostertag, W.; Bartram, C.
R.; Wiedemann, L. M.: The fusion of TEL and ABL in human acute lymphoblastic
leukaemia is a rare event. Brit. J. Haemat. 90: 222-224, 1995.

15. Knezevich, S. R.; McFadden, D. E.; Tao, W.; Lim, J. F.; Sorensen,
P. H. B.: A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nature
Genet. 18: 184-187, 1998.

16. Kobayashi, H.; Montgomery, K. T.; Bohlander, S. K.; Adra, C. N.;
Lim, B. L.; Kucherlapati, R. S.; Donis-Keller, H.; Holt, M. S.; Le
Beau, M. M.; Rowley, J. D.: Fluorescence in situ hybridization mapping
of translocations and deletions involving the short arm of human chromosome
12 in malignant hematologic diseases. Blood 84: 3473-3482, 1994.

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. Montpetit, A.; Sinnett, D.: Comparative analysis of the ETV6
gene in vertebrate genomes from pufferfish to human. Oncogene 20:
3437-3442, 2001.

19. Nilsson, T.; Andreasson, P.; Hoglund, M.; Fioretos, T.; Billstrom,
R.; Garwicz, S.; Mitelman, F.; Johansson, B.: ETV6/ABL fusion is
rare in Ph-negative chronic myeloid disorders. Leukemia 12: 1167-1168,
1998.

20. Odero, M. D.; Carlson, K.; Calasanz, M. J.; Lahortiga, I.; Chinwalla,
V.; Rowley, J. D.: Identification of new translocations involving
ETV6 in hematologic malignancies by fluorescence in situ hybridization
and spectral karyotyping. Genes Chromosomes Cancer 31: 134-142,
2001.

21. Odero, M. D.; Vizmanos, J. L.; Roman, J. P.; Lahortiga, I.; Panizo,
C.; Calasanz, M. J.; Zeleznik-Le, N. J.; Rowley, J. D.; Novo, F. J.
: A novel gene, MDS2, is fused to ETV6/TEL in a t(1;12)(p36.1;p13)
in a patient with myelodysplastic syndrome. Genes Chromosomes Cancer 35:
11-19, 2002.

22. Papadopoulos, P.; Ridge, S. A.; Boucher, C. A.; Stocking, C.;
Wiedemann, L. M.: The novel activation of ABL by fusion to an ets-related
gene, TEL. Cancer Res. 55: 34-38, 1995.

23. 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.

24. Penas, E. M. M.; Cools, J.; Algenstaedt, P.; Hinz, K.; Seeger,
D.; Schafhausen, P.; Schilling, G.; Marynen, P.; Hossfeld, D. K.;
Dierlamm, J.: A novel cryptic translocation t(12;17)(p13;p12-p13)
in a secondary acute myeloid leukemia results in a fusion of the ETV6
gene and the antisense strand of the PER1 gene. Genes Chromosomes
Cancer 37: 79-83, 2003.

25. Pierce, A.; Carney, L.; Hamza, H. G.; Griffiths, J. R.; Zhang,
L.; Whetton, B. A.; Gonzalez Sanchez, M. B.; Tamura, T.; Sternberg,
D.; Whetton, A. D.: THOC5 spliceosome protein: a target for leukaemogenic
tyrosine kinases that affects inositol lipid turnover. Brit. J. Haemat. 141:
641-650, 2008.

26. Raynaud, S. D.; Baens, M.; Grosgeorge, J.; Rodgers, K.; Reid,
C. D. L.; Dainton, M.; Dyer, M.; Fuzibet, J. G.; Gratecos, N.; Taillan,
B.; Ayraud, N.; Marynen, P.: Fluorescence in situ hybridization analysis
of t(3;12)(q26;p13): a recurring chromosomal abnormality involving
the TEL gene (ETV6) in myelodysplastic syndromes. Blood 88: 682-689,
1996.

27. Romana, S. P.; Poirel, H.; Leconiat, M.; Flexor, M.-A.; Mauchauffe,
M.; Jonveaux, P.; Macintyre, E. A.; Berger, R.; Bernard, O. A.: High
frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood 86:
4263-4269, 1995.

28. Salomon-Nguyen, F.; Della-Valle, V.; Mauchauffe, M.; Busson-Le
Coniat, M.; Ghysdael, J.; Berger, R.; Bernard, O. A.: The t(1;12)(q21;p13)
translocation of human acute myeloblastic leukemia results in a TEL-ARNT
fusion. Proc. Nat. Acad. Sci. 97: 6757-6762, 2000.

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. Stegmaier, K.; Pendse, S.; Barker, G. F.; Bray-Ward, P.; Ward,
D. C.; Montgomery, K. T.; Krauter, K. S.; Reynolds, C.; Sklar, J.;
Donnelly, M.; Bohlander, S. K.; Rowley, J. D.; Sallan, S. E.; Gilliland,
D. G.; Golub, T. R.: Frequent loss of heterozygosity at the TEL gene
locus in acute lymphoblastic leukemia of childhood. Blood 86: 38-44,
1995.

31. Tsuzuki, S.; Seto, M.; Greaves, M.; Enver, T.: Modeling first-hit
functions of the t(12;21) TEL-AML1 translocation in mice. Proc. Nat.
Acad. Sci. 101: 8443-8448, 2004.

32. Wang, L. C.; Kuo, F.; Fujiwara, Y.; Gilliland, D. G.; Golub, T.
R.; Orkin, S. H.: Yolk sac angiogenic defect and intra-embryonic
apoptosis in mice lacking the Ets-related factor TEL. EMBO J. 16:
4374-4383, 1997.

33. Wang, L. C.; Swat, W.; Fujiwara, Y.; Davdison, L.; Visvader, J.;
Kuo, F.; Alt, F. W.; Gilliland, D. G.; Golub, T. R.; Orkin, S. H.
: The TEL/ETV6 gene is required specifically for hematopoiesis in
the bone marrow. Genes Dev. 12: 2392-2401, 1998.

34. Yagasaki, F.; Jinnai, I.; Yoshida, S.; Yokoyama, Y.; Matsuda,
A.; Kusumoto, S.; Kobayashi, H.; Terasaki, H.; Ohyashiki, K.; Asou,
N.; Murohashi, I.; Bessho, M.; Hirashima, K.: Fusion of TEL/ETV6
to a novel ACS2 in myelodysplastic syndrome and acute myelogenous
leukemia with t(5;12)(q31;p13). Genes Chromosomes Cancer 26: 192-202,
1999.

*FIELD* CN
Ada Hamosh - updated: 6/10/2011
Marla J. F. O'Neill - updated: 6/10/2009
Patricia A. Hartz - updated: 4/16/2009
Cassandra L. Kniffin - updated: 12/5/2008
Marla J. F. O'Neill - updated: 4/12/2006
Patricia A. Hartz - updated: 7/2/2004
Victor A. McKusick - updated: 7/18/2003
Patricia A. Hartz - updated: 10/17/2002
Victor A. McKusick - updated: 10/14/2002
Victor A. McKusick - updated: 9/16/2002
Victor A. McKusick - updated: 8/7/2001
Victor A. McKusick - updated: 6/21/2001
Stylianos E. Antonarakis - updated: 10/11/2000
Victor A. McKusick - updated: 5/5/2000
Victor A. McKusick - updated: 1/6/2000
Victor A. McKusick - updated: 11/4/1998
Victor A. McKusick - updated: 9/2/1998
Victor A. McKusick - updated: 5/21/1998
Victor A. McKusick - updated: 1/26/1998
Victor A. McKusick - updated: 11/5/1997

*FIELD* CD
Victor A. McKusick: 9/18/1995

*FIELD* ED
terry: 11/29/2012
alopez: 6/20/2011
terry: 6/10/2011
wwang: 6/12/2009
terry: 6/10/2009
mgross: 4/16/2009
wwang: 12/16/2008
ckniffin: 12/5/2008
wwang: 4/12/2006
terry: 4/12/2006
wwang: 6/17/2005
wwang: 6/8/2005
terry: 6/7/2005
mgross: 7/14/2004
terry: 7/2/2004
mgross: 2/3/2004
tkritzer: 7/30/2003
terry: 7/18/2003
carol: 6/23/2003
mgross: 5/30/2003
mgross: 10/17/2002
tkritzer: 10/14/2002
carol: 10/3/2002
ckniffin: 10/3/2002
tkritzer: 9/25/2002
tkritzer: 9/16/2002
mcapotos: 8/10/2001
mcapotos: 8/9/2001
terry: 8/7/2001
terry: 6/21/2001
carol: 1/26/2001
terry: 1/25/2001
mgross: 10/11/2000
carol: 8/30/2000
mcapotos: 8/28/2000
mcapotos: 8/9/2000
mgross: 5/5/2000
mcapotos: 4/25/2000
mgross: 1/19/2000
terry: 1/6/2000
carol: 11/12/1998
terry: 11/4/1998
alopez: 9/2/1998
terry: 6/16/1998
terry: 5/21/1998
mark: 1/26/1998
terry: 1/26/1998
terry: 11/5/1997
jamie: 5/29/1997
jenny: 12/23/1996
terry: 12/17/1996
mark: 10/3/1996
terry: 9/9/1996
mark: 4/1/1996
mimadm: 11/3/1995
mark: 9/18/1995

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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2012.

*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