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Central to the discussion are key emerging genes such as\n                    <jats:italic>ASXL1<\/jats:italic>\n                    ,\n                    <jats:italic>SRSF2<\/jats:italic>\n                    , and\n                    <jats:italic>EZH2<\/jats:italic>\n                    , which are recognized as adverse prognostic markers. Mutations in these genes, coupled with subsequent alterations in epigenetic mechanisms, disrupt normal gene expression by impairing histone modification and RNA splicing processes. Specifically, mutations in ASXL1 enhance removal of ubiquitylation at histone H2AK119, leading to altered gene expression and impaired hematopoietic stem cell differentiation. Mutations in SRSF2, an RNA splicing factor, alter RNA-binding specificity, inducing aberrant splicing of key genes such as\n                    <jats:italic>EZH2<\/jats:italic>\n                    . Loss-of-function mutations in EZH2 disrupt PRC2-mediated transcriptional repression, promoting leukemic progression. However, while the effects of these mutations are understood, treatment options for high-risk patients remain limited. Emerging strategies, such as venetoclax combined with hypomethylating agents, showing promise in mitigating the poor prognosis associated with these mutations. This review consolidates recent findings on these epigenetic regulators and their interactions, providing insights into the multifaceted mechanisms of leukemogenesis in the interest of inspiring targeted therapeutic strategies and bridging extant treatment gaps for MDS\/AML.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02657-9","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T06:03:28Z","timestamp":1750831408000},"page":"2329-2339","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The role of ASXL1, SRSF2, and EZH2 mutations in chromatin dysregulation of myelodysplastic neoplasia and acute myeloid leukemia"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3069-036X","authenticated-orcid":false,"given":"Hosang","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7829-397X","authenticated-orcid":false,"given":"Junshik","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Yeop","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0643-0100","authenticated-orcid":false,"given":"Chul-Hwan","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"2657_CR1","doi-asserted-by":"crossref","unstructured":"Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J, et al. 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