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In this study, we identify CaMKII\u03b4 as a novel vulnerability in AML. CaMKII\u03b4 is aberrantly overactivated in primary and relapsed\/refractory AML patient samples compared with healthy donor peripheral blood mononuclear cells, with elevated expression correlating with increased tumor burden and inferior survival. Mechanistically, CaMKII\u03b4 inhibition induces rapid apoptosis in AML bulk and stem\/progenitor cells by suppressing STAT3 phosphorylation, downregulating CDK6-mediated cell cycle progression, and reducing BCL-2\u2013dependent survival. Strikingly, pharmacological blockade of CaMKII\u03b4 using the small-molecule inhibitor hesperadin effectively eliminates AML cells in vitro and achieves sustained disease regression in AML xenograft mouse models. Our findings establish CaMKII\u03b4 as a central regulator of AML cell survival and apoptosis, providing a preclinical rationale for targeting CaMKII\u03b4 to overcome therapy resistance in AML.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf184","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T12:46:19Z","timestamp":1766493979000},"source":"Crossref","is-referenced-by-count":1,"title":["Targeting CaMKII\u03b4 overcomes therapy resistance in acute myeloid leukemia by suppressing the STAT3\/CDK6\/BCL-2 survival axis"],"prefix":"10.1093","volume":"118","author":[{"given":"Zhaoxing","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Hematology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, College of Medicine"},{"name":"Cancer Institute, Zhejiang University , Hangzhou 310009 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