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

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.