Disruption of cotranscriptional splicing suggests RBM39 is a therapeutic target in acute lymphoblastic leukemia.

ABSTRACT:

Abstract

There are only a few options for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), thus, this is a major area of unmet medical need. In this study, we reveal that the inclusion of a poison exon in RBM39, which could be induced by both CDK9 or CDK9 independent cyclin-dependent kinases, mitogen-activated protein kinases, glycogen synthase kinases, CDC-like kinases (CMGC) kinase inhibition, is recognized by the nonsense-mediated messenger RNA decay pathway for degradation. Targeting this poison exon in RBM39 with CMGC inhibitors led to protein downregulation and the inhibition of ALL growth, particularly in relapsed/refractory B-ALL. Mechanistically, disruption of cotranscriptional splicing by the inhibition of CMGC kinases, including DYRK1A, or i

SUBMITTER: Jin Q 

PROVIDER: S-EPMC11628860 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature