{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:14:09Z","timestamp":1792088049478,"version":"4.4.0"},"reference-count":37,"publisher":"Rockefeller University Press","issue":"12","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,11,18]]},"abstract":"<jats:p>Polycomb group (PcG) proteins are essential regulators of hematopoietic stem cells. Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS\/myeloproliferative neoplasm (MPN) overlap disorders (MDS\/MPN). In our patient cohort, EZH2 mutations were also found and often coincided with tet methylcytosine dioxygenase 2 (TET2) mutations. Consistent with these findings, deletion of Ezh2 alone was enough to induce MDS\/MPN-like diseases in mice. Furthermore, concurrent depletion of Ezh2 and Tet2 established more advanced myelodysplasia and markedly accelerated the development of myelodysplastic disorders including both MDS and MDS\/MPN. Comprehensive genome-wide analyses in hematopoietic progenitor cells revealed that upon deletion of Ezh2, key developmental regulator genes were kept transcriptionally repressed, suggesting compensation by Ezh1, whereas a cohort of oncogenic direct and indirect polycomb targets became derepressed. Our findings provide the first evidence of the tumor suppressor function of EZH2 in myeloid malignancies and highlight the cooperative effect of concurrent gene mutations in the pathogenesis of myelodysplastic disorders.<\/jats:p>","DOI":"10.1084\/jem.20131144","type":"journal-article","created":{"date-parts":[[2013,11,11]],"date-time":"2013-11-11T23:07:48Z","timestamp":1384211268000},"page":"2627-2639","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":180,"title":["Concurrent loss of\n                    <i>Ezh2<\/i>\n                    and\n                    <i>Tet2<\/i>\n                    cooperates in the pathogenesis of myelodysplastic disorders"],"prefix":"10.1084","volume":"210","author":[{"given":"Tomoya","family":"Muto","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Department of Hematology, Chiba University Hospital, Chiba 260-8670, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goro","family":"Sashida","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Japan Science and Technology Corporation (JST), Core Research for Evolutional Science and Technology (CREST), Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motohiko","family":"Oshima","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Japan Science and Technology Corporation (JST), Core Research for Evolutional Science and Technology (CREST), Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George R.","family":"Wendt","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"ITO Foundation for International Education Exchange, Shinjuku 160-0023, Japan 10"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Mochizuki-Kashio","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Japan Science and Technology Corporation (JST), Core Research for Evolutional Science and Technology (CREST), Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunobu","family":"Nagata","sequence":"additional","affiliation":[{"name":"Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Sanada","sequence":"additional","affiliation":[{"name":"Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Miyagi","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Japan Science and Technology Corporation (JST), Core Research for Evolutional Science and Technology (CREST), Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsunori","family":"Saraya","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Japan Science and Technology Corporation (JST), Core Research for Evolutional Science and Technology (CREST), Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asuka","family":"Kamio","sequence":"additional","affiliation":[{"name":"Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genta","family":"Nagae","sequence":"additional","affiliation":[{"name":"Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaki","family":"Nakaseko","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Department of Hematology, Chiba University Hospital, Chiba 260-8670, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koutaro","family":"Yokote","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Shimoda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Miyazaki 889-1692, Japan 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Koseki","sequence":"additional","affiliation":[{"name":"Japan Science and Technology Corporation (JST), Core Research for Evolutional Science and Technology (CREST), Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan 4"},{"name":"Laboratory for Lymphocyte Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba 277-8562, Japan 9"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumio","family":"Sugano","sequence":"additional","affiliation":[{"name":"Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba 277-8562, Japan 9"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Aburatani","sequence":"additional","affiliation":[{"name":"Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seishi","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Iwama","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine 1 and 2"},{"name":"Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan 1 and 2"},{"name":"Japan Science and Technology Corporation (JST), Core Research for Evolutional Science and Technology (CREST), Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2013,11,11]]},"reference":[{"key":"2023072601211144700_bib1","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1038\/leu.2011.58","article-title":"Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms","volume":"25","author":"Abdel-Wahab","year":"2011","journal-title":"Leukemia."},{"key":"2023072601211144700_bib2","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.ccr.2012.06.032","article-title":"ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression","volume":"22","author":"Abdel-Wahab","year":"2012","journal-title":"Cancer Cell."},{"key":"2023072601211144700_bib3","doi-asserted-by":"publisher","first-page":"2496","DOI":"10.1056\/NEJMoa1013343","article-title":"Clinical effect of point mutations in myelodysplastic syndromes","volume":"364","author":"Bejar","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"2023072601211144700_bib4","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.cell.2006.02.041","article-title":"A bivalent chromatin structure marks key developmental genes in embryonic stem cells","volume":"125","author":"Bernstein","year":"2006","journal-title":"Cell."},{"key":"2023072601211144700_bib5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/ng.1009","article-title":"Dnmt3a is essential for hematopoietic stem cell differentiation","volume":"44","author":"Challen","year":"2012","journal-title":"Nat. Genet."},{"key":"2023072601211144700_bib6","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1038\/nature07399","article-title":"Oncogenic mutations of ALK kinase in neuroblastoma","volume":"455","author":"Chen","year":"2008","journal-title":"Nature."},{"key":"2023072601211144700_bib7","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1007\/s12185-012-1181-z","article-title":"Epigenetic alterations in hematopoietic malignancies","volume":"96","author":"Chung","year":"2012","journal-title":"Int. J. Hematol."},{"key":"2023072601211144700_bib8","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1126\/science.1221711","article-title":"Loss of the tumor suppressor BAP1 causes myeloid transformation","volume":"337","author":"Dey","year":"2012","journal-title":"Science."},{"key":"2023072601211144700_bib9","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/ng.621","article-title":"Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders","volume":"42","author":"Ernst","year":"2010","journal-title":"Nat. Genet."},{"key":"2023072601211144700_bib10","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/ncomms1623","article-title":"Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease","volume":"3","author":"Herrera-Merchan","year":"2012","journal-title":"Nat Commun."},{"key":"2023072601211144700_bib11","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.stem.2012.08.001","article-title":"Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest","volume":"11","author":"Hidalgo","year":"2012","journal-title":"Cell Stem Cell."},{"key":"2023072601211144700_bib12","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.cell.2010.09.010","article-title":"A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs","volume":"143","author":"Kim","year":"2010","journal-title":"Cell."},{"key":"2023072601211144700_bib13","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/nature09586","article-title":"Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2","volume":"468","author":"Ko","year":"2010","journal-title":"Nature."},{"key":"2023072601211144700_bib14","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1111\/j.1440-169X.2010.01191.x","article-title":"Role of the polycomb group proteins in hematopoietic stem cells","volume":"52","author":"Konuma","year":"2010","journal-title":"Dev. Growth Differ."},{"key":"2023072601211144700_bib15","doi-asserted-by":"publisher","first-page":"e1000242","DOI":"10.1371\/journal.pgen.1000242","article-title":"Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains","volume":"4","author":"Ku","year":"2008","journal-title":"PLoS Genet."},{"key":"2023072601211144700_bib16","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1182\/blood-2012-07-442004","article-title":"PBX3 is an important cofactor of HOXA9 in leukemogenesis","volume":"121","author":"Li","year":"2013","journal-title":"Blood."},{"key":"2023072601211144700_bib17","doi-asserted-by":"publisher","first-page":"6553","DOI":"10.1182\/blood-2011-03-340554","article-title":"Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells","volume":"118","author":"Mochizuki-Kashio","year":"2011","journal-title":"Blood."},{"key":"2023072601211144700_bib18","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ccr.2011.06.001","article-title":"Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation","volume":"20","author":"Moran-Crusio","year":"2011","journal-title":"Cancer Cell."},{"key":"2023072601211144700_bib19","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/ng.518","article-title":"Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin","volume":"42","author":"Morin","year":"2010","journal-title":"Nat. Genet."},{"key":"2023072601211144700_bib20","doi-asserted-by":"publisher","first-page":"6071","DOI":"10.1158\/0008-5472.CAN-05-0465","article-title":"A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays","volume":"65","author":"Nannya","year":"2005","journal-title":"Cancer Res."},{"key":"2023072601211144700_bib21","doi-asserted-by":"publisher","first-page":"5028","DOI":"10.1073\/pnas.1202258109","article-title":"Polycomb repressive complex 2 is required for MLL-AF9 leukemia","volume":"109","author":"Neff","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072601211144700_bib22","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/ng.620","article-title":"Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes","volume":"42","author":"Nikoloski","year":"2010","journal-title":"Nat. Genet."},{"key":"2023072601211144700_bib23","doi-asserted-by":"publisher","first-page":"2247","DOI":"10.1084\/jem.20052477","article-title":"Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice","volume":"203","author":"Oguro","year":"2006","journal-title":"J. Exp. Med."},{"key":"2023072601211144700_bib24","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.stem.2010.01.005","article-title":"Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the polycomb protein Bmi1","volume":"6","author":"Oguro","year":"2010","journal-title":"Cell Stem Cell."},{"key":"2023072601211144700_bib25","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1084\/jem.20111709","article-title":"Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes","volume":"209","author":"Oguro","year":"2012","journal-title":"J. Exp. Med."},{"key":"2023072601211144700_bib26","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1093\/bioinformatics\/19.2.295","article-title":"Matrix2png: a utility for visualizing matrix data","volume":"19","author":"Pavlidis","year":"2003","journal-title":"Bioinformatics."},{"key":"2023072601211144700_bib27","doi-asserted-by":"publisher","first-page":"D61","DOI":"10.1093\/nar\/gkl842","article-title":"NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins","volume":"35","author":"Pruitt","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"2023072601211144700_bib28","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1038\/nrc3321","article-title":"The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes","volume":"12","author":"Raza","year":"2012","journal-title":"Nat. Rev. Cancer."},{"key":"2023072601211144700_bib29","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/nature11323","article-title":"IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics","volume":"488","author":"Sasaki","year":"2012","journal-title":"Nature."},{"key":"2023072601211144700_bib30","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.stem.2010.08.002","article-title":"Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer","volume":"7","author":"Sauvageau","year":"2010","journal-title":"Cell Stem Cell."},{"key":"2023072601211144700_bib31","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.molcel.2008.10.016","article-title":"EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency","volume":"32","author":"Shen","year":"2008","journal-title":"Mol. Cell."},{"key":"2023072601211144700_bib32","doi-asserted-by":"publisher","first-page":"2216","DOI":"10.1038\/leu.2012.94","article-title":"TET2 is essential for survival and hematopoietic stem cell homeostasis","volume":"26","author":"Shide","year":"2012","journal-title":"Leukemia."},{"key":"2023072601211144700_bib33","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/nrc3343","article-title":"The role of mutations in epigenetic regulators in myeloid malignancies","volume":"12","author":"Shih","year":"2012","journal-title":"Nat. Rev. Cancer."},{"key":"2023072601211144700_bib34","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072601211144700_bib35","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1182\/blood-2011-11-394932","article-title":"Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia","volume":"120","author":"Tanaka","year":"2012","journal-title":"Blood."},{"key":"2023072601211144700_bib36","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1101\/gad.1897910","article-title":"Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes","volume":"24","author":"Tremblay","year":"2010","journal-title":"Genes Dev."},{"key":"2023072601211144700_bib37","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1086\/518809","article-title":"Highly sensitive method for genomewide detection of allelic composition in nonpaired, primary tumor specimens by use of affymetrix single-nucleotide-polymorphism genotyping microarrays","volume":"81","author":"Yamamoto","year":"2007","journal-title":"Am. J. Hum. Genet."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/210\/12\/2627\/1745873\/jem_20131144.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/210\/12\/2627\/1745873\/jem_20131144.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T21:21:34Z","timestamp":1690320094000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/210\/12\/2627\/53782\/Concurrent-loss-of-Ezh2-and-Tet2-cooperates-in-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,11,11]]},"references-count":37,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2013,11,18]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20131144","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718173279.793487516","asserted-by":"object"}]},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2013,11,11]]}}}