Evaluating splicing modulators for therapeutic impact in cohesin-mutant AML and MDS cells

Cohesin is a multi-subunit protein complex that forms a ring-like structure around DNA. Cohesin is essential for sister chromatid cohesion, chromosome organization into looped domains, DNA damage repair and transcription regulation. Germline loss-of-function mutations in cohesin subunits cause a family of developmental disorders termed cohesinopathies. In addition, cohesin is one of the most frequently mutated protein complexes in cancer, including myeloid blood cancers, with recurrent somatic loss-of-function mutations in core components of the cohesin ring and its modulators. Importantly, cancer-associated mutations in cohesin rarely affect chromosome integrity, but instead selectively impair chromatin organization and gene-regulatory functions. However, how cohesin affects gene activity remains enigmatic, offering no clues towards intervention. Consequently, there are no targeted therapeutic approaches available to treat disease involving cohesin mutations. Recently, we discovered that cohesin mutations common in myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) disrupt both transcription and RNA splicing. Through detailed investigation of gene activity and splicing profiles in cohesin-mutant AML cells, we hope to discover novel opportunities for therapeutic targeting. Our goal is to leverage this knowledge to develop targeted approaches that will selectively kill cohesin-mediated disease. The findings from these studies have the potential to lead directly to one or more clinical trials within the next several years.