Transcriptome of MLL-AF9 blast sensitive and resistant to chemotherapy

Using multi-omic profiling and in vivo functional genomics, we identified splicing perturbations as a major determinant of chemoresistance in AML. We pinpointed a splicing-associated network involving the splicing regulator SRRM1 and two kinases, CLK and PAK1, as critical vulnerabilities in chemoresistant AML cells.

Both kinases are hyperactivated in chemoresistant AML cells and we discovered a point variant in PAK1, c.1429G>T p.(Ala477Ser), that conferred resistance to chemotherapy in a patient undergoing relapse post-treatment. Combinatory inhibition of PAK1 and CLK kinases exhibited partially similar splicing perturbations to SRRM1 loss, preferentially targeting chemoresistant AML cell lines, primary cells, and multiple mouse models of AML and potentiating anti-leukemic effects of chemotherapy.