Therapeutic approaches targeting splicing factor mutations in myelodysplastic syndromes and acute myeloid leukemia.

Purpose Of Review: Mutations in components of the spliceosome are the most common acquired lesions in myelodysplastic syndromes (MDS) and are frequently identified in other myeloid malignancies with a high rate of progression to acute myeloid leukemia (AML) including chronic myelomonocytic leukemia and primary myelofibrosis. The only curative option for these disorders remains allogeneic stem-cell transplantation, which is associated with high morbidity and mortality in these patients. The purpose of this review is to highlight the recent therapeutic developments and strategies being pursued for clinical benefit in splicing factor mutant myeloid malignancies.

Recent Findings: Cells harboring splicing factor mutations have increased aberrant splicing leading to R-loop formation and cell cycle stalling that create dependencies on Checkpoint kinase 1 (CHK1) activation and canonical splicing maintained by protein arginine methyltransferase activity. Both targeting of the spliceosome and targeting of the downstream consequences of splicing factor mutation expression show promise as selective strategies for the treatment of splicing factor-mutant myeloid malignancies.

Summary: An improved understanding of the therapeutic vulnerabilities in splicing factor-mutant MDS and AML has led to the development of clinical trials of small molecule inhibitors that target the spliceosome, ataxia telangectasia and Rad3 related (ATR)-CHK1 pathway, and methylation of splicing components.