Targeting Y593-phosphorylated DDX5 triggers mitochondrial dysfunction and synergizes with BCL2 inhibition in acute myeloid leukemia

Acute myeloid leukemia (AML) remains a lethal malignancy with limited therapeutic durability. DEAD-box RNA helicase 5 (DDX5) is highly expressed in AML and associated with poor outcome, yet its mechanistic role and therapeutic tractability are incompletely defined. Here, we identify phosphorylation at tyrosine 593 (Y593) of DDX5 as a therapeutic vulnerability in AML. We show that DDX5 is constitutively phosphorylated at Y593 in AML cells independent of Src or c-Abl activity. While genetic depletion of DDX5 suppresses AML growth, phosphorylation-deficient Y593F knock-in mutants show that Y593 phosphorylation is dispensable for baseline proliferation but is required to maintain mitochondrial integrity and define the BCL-2 family–controlled apoptotic threshold. Targeting Y593-phosphorylated DDX5 with the small-molecule RX-5902 destabilizes β-catenin and, more importantly, triggers acute mitochondrial dysfunction characterized by impaired oxidative phosphorylation, permeabilizes mitochondrial outer membranes, and increases BCL-2 dependence. Accordingly, inhibition of Y593-phosphorylated DDX5 represents a mitochondrial sensitizer that creates vulnerability to BCL-2 blockade. Consistent with this mechanism, RX-5902 strongly synergizes with venetoclax across AML cell lines, primary patient samples, and xenograft models. Together, these findings establish Y593-phosphorylated DDX5 as an actionable regulator of mitochondrial apoptotic priming in AML and support combined targeting of DDX5 and BCL-2 as a rational therapeutic strategy.