Targeting PRMT9 Overcomes Venetoclax Resistance In AML By Modulation Splicing And Inhibiting Translation

Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is critical for promoting acute myeloid leukemia (AML) growth. But its role in BCL2 inhibitor venetoclax resistance (VEN-R) remains elusive. Here, through a loss-of-function screen in VEN-R primary AML patient-derived xenograft (PDX) cells and cell lines, we identified PRMT9 as a critical regulator to promote VEN resistance. Among PRMTs, PRMT9 is preferentially overexpressed in VEN-R AML cell lines and samples, and its inhibition re-sensitized the cells to VEN treatment. We further report synergy of a PRMT9 inhibitor LD2 with VEN in eradicating resistant AML in preclinical models. Mechanistically, PRMT9 ablation in VEN-R cells disrupted RNA splicing by inducing exon skipping of key regulators such as ALG13, eventually leading to downregulation of ATP-binding transporter encoded by ABCC1 responsible for VEN efflux. Concurrently, PRMT9 inhibition suppressed protein translation, resulting in the degradation of short-lived oncoproteins, including MCL1. These findings establish a critical role for PRMT9-mediated arginine methylation in promoting VEN-R and highlight the potency of combining PRMT9 inhibition with VEN as a novel therapeutic strategy against AML.