INVESTIGATING THE EFFECT OF PRMT INHIBITORS ON MYELOID LEUKEMIAS WITH SPLICEOSOMAL GENE MUTATIONS

Abstract

Mutations in RNA-splicing factors occur at high frequency in myelodysplastic syndromes and are also found in leukemias and solid cancers. The most commonly mutated splicing factors include SRSF2, SF3B1, U2AF1 and ZRSR2. These mutations occur in a heterozygous and mutually exclusive manner, suggesting that cells cannot tolerate the perturbation of splicing beyond a single allele mutation. These observations have fuelled recent clinical efforts to directly target and inhibit components of the splicing machinery in patients with refractory leukemias. Inhibition of type I PRMT and PRMT5 is shown here, to cause splicing perturbation and preferentially kill splicing factor mutant leukemias over their wildtype counterparts. The data identifies genetic subsets of cancer most likely to be susceptible to PRMT inhibition, highlights the synergistic effects of combinatorial use of Type I PRMT and PRMT5 inhibitors and provides a mechanistic basis for therapeutic efficacy of PRMT inhibition in cancer.