Targeting PRMT9 Overcomes Venetoclax Resistance in AML by Modulating Splicing and Inhibiting Translation

Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is required for cancer cell proliferation, but whether PRMTs mediate resistance to therapy remains elusive. Here, we have performed loss-of-function screens in venetoclax-resistant (VEN-R) AML patient-derived xenograft (PDX) cells and found that PRMT9 plays a critical role in promoting VEN resistance. Specifically, VEN-R AML samples exhibited high levels of PRMT9, and PRMT9 inhibition re-sensitized the AML cells to VEN treatment. In preclinical resistant models, genetic ablation of PRMT9 synergized with VEN to eradicate AML cells. Consistently, pharmacologic inhibition of PRMT9 combined with VEN yielded similar effects in VEN-R AML mouse models. Mechanistically, PRMT9 ablation disrupted RNA splicing by inducing exon-skipping of mRNA encoding ALG13, an UDP-N-Acetylglucosaminyltransferase subunit, downregulating expression of a VEN-efflux transporter encoded by the adenosine triphosphate binding cassette subfamily C member 1 (ABCC1) gene. PRMT9 inhibition also suppressed protein synthesis, downregulating short-lived oncoproteins, such as MCL1. These findings establish a connection between PRMT9-mediated arginine methylation and poor VEN responsiveness, also demonstrate that targeting PRMT9 may represent a viable strategy to overcome VEN resistance.