PROJECT SUMMARY

In this project, we have focused on a specific subtype of human blood disease called myelodysplastic syndrome (MDS), which is characterized by mutations in a protein complex called the cohesin complex. This complex forms a ring like structure around DNA and is very important for normal functions of every cell, including the process of copying, repairing and folding the genetic material inside of the nucleus of each cell. Using human patient samples that carry mutations in the cohesin complex, we have previously discovered that cohesin-mutant cells are unable to repair errors that occur in DNA when it is being copied or used as a master plan to make proteins. The goal of this project was to (1) study whether combination of two drugs with distinct activity – a PARP inhibitor talazoparib and a hypomethylating agent azacitidine could effectively kill cohesin-mutant cells, and (2) to investigate whether transcription-related stress in the form of R loop formation contributes to DNA damage formation in cohesin-mutant cells. Our data demonstrate that combination of PARP inhibition and hypomethylating agents is an effective combination therapy for cohesin-mutant myeloid malignancies, which has now been translated to a clinical trial of combination treatment of decitabine and talazoparib in cohesin-mutant MDS/AML. Furthermore, we demonstrated that R loop accumulation in both in vitro and in vivo models of cohesin-mutant MDS and AML is associated with DNA damage accumulation and are further investigating this as a potential feature to target.