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LSCs are characterized as self\u2010renewing and highly proliferative cancer stem cells and accumulate abnormal genetic and epigenetic factors contributing to their uncontrolled proliferation. Chromosomal translocation t(9;11)(p22;q23) forms fusion oncoprotein, MLL\u2010AF9, and regulates the transcription factor, C\u2010Myb, which is highly expressed in AML. C\u2010Myb regulates polycomb protein, EzH2, but this is still unexplored in MLL\u2010AF9\u2010induced AML, which highly expresses CD123. The active targeting with epigenetic regulation of EzH2 in MLL\u2010AF9\u2010rearranged AML can provide novel translational potential for anti\u2010AML therapeutics. So, CD123\u2010targeted delivery of EzH2 siRNA is hypothesized through ZW25 aptamer\u2010functionalized human serum albumin nanoparticles (si\u2010EzH2@HNPs@ZW25) for enhanced anti\u2010AML therapeutics in MLL\u2010AF9\u2010induced in vitro and in vivo AML models. si\u2010EzH2@HNPs@ZW25 exhibit superior therapeutic efficacy under MLL\u2010AF9\u2010induced athymic xenografts with enhanced suppression of c\u2010Kit\n                    <jats:sup>+<\/jats:sup>\n                    LSCs, and stimulation of myeloid\u2010specific differentiation markers, CD11b and Gr\u20101. si\u2010EzH2@HNPs@ZW25 increased the survival of CD34\n                    <jats:sup>+<\/jats:sup>\n                    CD38\n                    <jats:sup>\u2212<\/jats:sup>\n                    AML patient\u2010derived xenograft mice and augmented the suppression of c\u2010Kit\n                    <jats:sup>+<\/jats:sup>\n                    LSCs and stimulation of CD11b and Gr\u20101. In MLL\u2010AF9 AML, C\u2010Myb directly regulates EzH2 through promoter binding wherein si\u2010EzH2@HNPs@ZW25 disrupt this functional\u00a0crosstalk in AML revealingfuture translational potential of si\u2010EzH2@HNPs@ZW25 as AML therapy.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202503118","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T06:12:04Z","timestamp":1757571124000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD123 Targeted Epigenetic Nanotherapy for Fusion Oncoprotein MLL\u2010AF9 Rearranged Acute Myeloid Leukemia in Preclinical and Patient Derived Xenograft Models"],"prefix":"10.1002","volume":"15","author":[{"given":"Avinash Chandra","family":"Kushwaha","sequence":"first","affiliation":[{"name":"Epigenetics Research Laboratory Institute of Nano Science and Technology  Knowledge City, Sector 81 Mohali Punjab 140306 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pankaj","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology and Medical Oncology Nehru Hospital Post\u2010Graduate Institute of Medical Education and Research  Room No 18, 4th Level, F Block Chandigarh 160020 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surajit","family":"Karmakar","sequence":"additional","affiliation":[{"name":"Institute of Nano Science and Technology  Knowledge City, Sector 81 Mohali Punjab 140306 India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7894-8297","authenticated-orcid":false,"given":"Subhasree","family":"Roy Choudhury","sequence":"additional","affiliation":[{"name":"Epigenetics Research Laboratory Institute of Nano Science and Technology  Knowledge City, Sector 81 Mohali Punjab 140306 India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516192"},{"key":"e_1_2_10_2_1","first-page":"2099","volume":"107","author":"Deschler B.","year":"2006","journal-title":"J. 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