Clinical Implications of Spliceosome Mutations: Epidemiology, Clonal Hematopoiesis, and Potential Therapeutic Strategies

Somatic mutations in genes that are involved in pre-mRNA splicing (i.e., spliceosome genes) occur in ~50% of patients with myelodysplastic syndromes (MDS). Commonly mutated spliceosome genes (e.g., SF3B1, SRSF2, and U2AF1)have variable prognostic significance in patients with myeloid malignancies. For example, SRSF2 and U2AF1 mutations are associated with worse and SF3B1 mutations with better clinical outcomes compared to patients without a spliceosome gene mutation. While multiple groups have shown that RNA splicing is altered in patients with spliceosome gene mutations, the contribution of these alterations to disease pathogenesis is largely unknown. Several groups have recently reported that RNA splicing and hematopoiesis are altered in mutant expressing mouse models, providing direct evidence that spliceosome gene mutations contribute to some MDS phenotypes. Spliceosome gene mutations have also been detected in the blood cells of healthy elderly individuals with clonal hematopoiesis who are at an increased risk of developing hematopoietic cancer, further implicating these mutations as early genetic drivers in MDS. Consistent with this possibility, spliceosome gene mutations tend to occur in the founding clone (i.e., present in every tumor cell in a patient) of myeloid malignancies. Collectively, these observations indicate that targeting mutant cells could have a large clinical impact. Several observations indicate that spliceosome gene mutations may create a genetic vulnerability in cells that could be exploited therapeutically. Spliceosome gene mutations are typically heterozygous and mutually exclusive of each other in patients, implying either a redundancy in pathogenic function of mutant genes or that a cell cannot tolerate two spliceosome perturbations at once. Accumulating evidence now suggests that heterozygous mutant cells require appropriate expression levels of the non-mutant residual allele or other splicing factors to maintain cell viability. Therefore, we and others hypothesize that cells harboring spliceosome mutations will have increased sensitivity to pharmacological perturbation of the spliceosome, providing a new treatment approach for patients with these mutations. To examine this, we used sudemycin compounds that bind the SF3B1 protein to modulate pre-mRNA splicing. We show that treatment of U2AF1 mutant mice with sudemycin results in attenuation of mutant-associated hematopoietic progenitor cell expansion compared to control treated mice. Collectively, data from our group and others suggest that cells expressing mutant spliceosome genes have an increased sensitivity to pharmacologic perturbation of splicing. Clinical trials are being designed to treat spliceosome mutant hematological cancers with splicing modulator compounds.