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However, the role of SETD2 in\n                    <jats:italic>MLL\u2010<\/jats:italic>\n                    fusion leukemia has remained controversial over the past decade. Here, through genotyping of loss\u2010of\u2010function SETD2 mutations, we define the genetic basis for SETD2 acting as a haploinsufficient tumor suppressor in this disease. Then, we demonstrate that gene amplification and high expression of\n                    <jats:italic>SETD2<\/jats:italic>\n                    are associated with poor prognosis, supporting the double\u2010sided roles of\n                    <jats:italic>SETD2<\/jats:italic>\n                    in this kind of acute leukemia. Next, we show that inhibitors of SETD2 (EZM0414) and menin (Revumenib) have synergistic efficacy against\n                    <jats:italic>MLL<\/jats:italic>\n                    \u2010fusion and\n                    <jats:italic>NPM1<\/jats:italic>\n                    \u2010mut leukemia and make prominent induction of cell cycle arrest, differentiation, and apoptosis. Moreover, SETD2 inhibition sensitizes leukemia cells to menin inhibitor through decreasing H3K36me3 marks, and combination therapy dramatically inhibits transcription of the canonical targeted genes, whose function may account for these phenotypic changes. The mode of action of this combined treatment is due to the attenuated both H3K36me3 at gene body regions and H3K4me3 at gene promoter regions. Finally, we clarify that the combined\u2010drug treatment delays\n                    <jats:italic>MLL<\/jats:italic>\n                    \u2010fusion leukemia progression in\u00a0vivo. Taken together, these findings establish the simultaneously blocking of transcription elongation and initiation by epigenetic inhibitors as a promising therapeutic strategy for these aggressive leukemias.\n                  <\/jats:p>","DOI":"10.1111\/cas.70419","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T11:36:21Z","timestamp":1779449781000},"page":"2221-2235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blocking\n                    <scp>SETD2<\/scp>\n                    Enhances the Therapeutic Efficiency of Menin Inhibitor in\n                    <scp>\n                      <i>MLL<\/i>\n                    <\/scp>\n                    \u2010Fusion Leukemia"],"prefix":"10.1111","volume":"117","author":[{"given":"Anpei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, School of Medicine Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anhao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Zhongshan Hospital of Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, School of Medicine Xiamen University  Xiamen Fujian 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