Targeting CaMKIIδ overcomes therapy resistance in acute myeloid leukemia by suppressing the STAT3/CDK6/BCL-2 survival axis.

Relapse and therapy resistance remain major barriers to improving clinical outcomes in acute myeloid leukemia (AML), underscoring the need for actionable therapeutic targets. In this study, we identify CaMKIIδ as a novel vulnerability in AML. CaMKIIδ 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, CaMKIIδ 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-dependent survival. Strikingly, pharmacological blockade of CaMKIIδ 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 CaMKIIδ as a central regulator of AML cell survival and apoptosis, providing a preclinical rationale for targeting CaMKIIδ to overcome therapy resistance in AML.