SRPK1_is_a_therapeutic_vulnerability_in_acute_myeloid_leukemia_through_its_effects_on_isoform_choice_of_epigenetic_regulators__

Acute myeloid leukemia (AML) is an aggressive cancer of hematopoietic stem cells that remains lethal for most sufferers. Having recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of AML, here we investigate the molecular basis and therapeutic potential of this finding. First, we show that genetic or pharmacological inhibition of SRPK1 induces cell cycle arrest, leukemic cell differentiation and prolongation of survival of immunocompromised mice transplanted with AML cells. We go on to show that SRPK1 inhibition led to altered isoform levels of many genes including several with roles in leukemogenesis such as MYB and MED24. Collectively our findings reveal that SRPK1 is required for normal splicing of key epigenetic regulators and forms a novel a therapeutic vulnerability in AML.