Splicing-associated network PAK1-CLK1/4-SRRM1 is a vulnerability to overcome chemoresistance in human and mouse acute myeloid leukemia.

Abstract

Chemotherapy resistance in acute myeloid leukemia (AML) remains a major clinical challenge. Integration of multiomic profiling and in vivo functional genomics revealed splicing dysregulation as a determinant of chemoresistance in AML. We uncovered a network involving the splicing regulator SRRM1 and the CLK1/4 and PAK1 kinase families as vulnerabilities in chemoresistant AML cells. Both kinase families are hyperactivated in chemoresistant cells, promoting SRRM1 phosphorylation and altering its scaffolding function. We also identified a relapse-associated <i>PAK1</i> variant, c.1429G>T p.(Ala⁴⁷⁷→Ser), that confers chemotherapy resistance. Combined PAK1 and CLK1/4 inhibition recapitulated the splicing changes induced by <i>SRRM1</i> loss, preferentially targeting chemoresistant AML and enhancing chemotherapy efficacy in cell lines, primary cells, and mouse models. Last, we pinpointed MAP2K5 as a critical downstream effector because missplicing of exons 17 and 18 of <i>MAP2K5</i> upon SRRM1 depletion sensitized cells to chemotherapy. Our findings highlight a therapeutic strategy to overcome AML relapse by targeting splicing dysregulation.