PAK4 phosphorylates and stabilizes MYC to promote acute myeloid leukemia.

MYC dysregulation plays a crucial role in acute myeloid leukemia (AML), yet the mechanisms governing its stabilization remain incompletely understood. MYC protein turnover is tightly regulated by post-translational modifications (PTMs), especially phosphorylation-dependent ubiquitination. Our previous study identified phosphorylation at MYC Serine 67 (S67) is critical to sustain its oncogenic activity in T-cell acute lymphoblastic leukemia (T-ALL). Here, we demonstrate that MYC S67 phosphorylation is also present in AML and catalyzed by p21-activated kinase 4 (PAK4). PAK4 directly binds MYC via its MBII domain, phosphorylates S67 and disrupts FBXW7-dependent ubiquitination, thereby stabilizing MYC to sustain MYC-driven leukemogenic programs. PAK4 inhibition destabilizes MYC and suppresses AML proliferation; however, it fails to elicit robust apoptosis, primarily due to the compensatory upregulation of the anti-apoptotic factor MCL-1. Combining the PAK4 inhibitor KPT-9274 with the MCL-1 antagonist S63845 induces synergistic lethality in AML cells. These findings provide the mechanistic insight of MYC stabilization in AML and establish a PAK4 inhibition-based targeted strategy as a promising therapeutic approach for AML treatment.