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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296895 | GEO | 2026/05/11

REPOSITORIES: GEO

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