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High throughput drug screens, CUT&amp;Tag\/RNA sequence, and functional assays using human MDS\/AML cells revealed that EZH2 inhibitors efficiently induce apoptosis preferentially in MDS\/AML with inv(3)\/t(3;3) and \u22127 through the activation of GADD45\u03b3\u2010p38\u2010p53 axis. EVI1 activated in 3q\u2010rearranged MDS\/AML was responsible for <jats:italic>GADD45\u03b3<\/jats:italic> silencing by direct binding to its consensus sequence within GADD45\u03b3 promoter and recruitment of PRC2 complex via interaction with EZH2, which can be therapeutically targeted by EZH2 inhibition. MDS\/AML with inv(3)\/t(3;3) and \u22127 showed preferential sensitivity to EZH2 inhibition in both mouse model and patient samples. Thus, MDS\/AML cells with inv(3)\/t(3;3) and \u22127 possess apoptosis evasion mechanism through EVI1\u2010PRC2\u2010mediated repression of GADD45\u03b3\u2010p38\u2010p53 axis, which is a potential therapeutic vulnerability in MDS\/AML patients with these high\u2010risk cytogenetic lesions.<\/jats:p>","DOI":"10.1002\/hem3.70149","type":"journal-article","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T09:08:41Z","timestamp":1752397721000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PRC2\u2010mediated apoptosis evasion is a therapeutic target of MDS\/AML harboring inv(3)\/t(3;3) and monosomy 7"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0511-2583","authenticated-orcid":false,"given":"Hiroyoshi","family":"Kunimoto","sequence":"first","affiliation":[{"name":"Department of Stem Cell and Immune Regulation Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayaka","family":"Miura","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Immune Regulation Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maiko","family":"Sagisaka","sequence":"additional","affiliation":[{"name":"Clinical Research Institute Kanagawa Children's Medical Center Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mieko","family":"Ito","sequence":"additional","affiliation":[{"name":"Clinical Research Institute Kanagawa Children's Medical Center Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryoichi","family":"Maenosono","sequence":"additional","affiliation":[{"name":"Division of Cancer RNA Research National Cancer Center Research Institute Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Division of Cancer RNA Research National Cancer Center Research Institute Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuki","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Division of Cancer RNA Research National Cancer Center Research Institute Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Honma","sequence":"additional","affiliation":[{"name":"Modality Research Laboratories III, Daiichi Sankyo Co. 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