MDS patients who are treated with hypomethylating agents (HMAs, the current standard of care for this disease) almost universally develop resistance to these drugs and subsequently progress to acute myeloid leukemia. Patients in whom the therapy has failed have dismal prognoses and poor complete response rates to standard therapy. Almost nothing is known about the mechanisms underlying HMA resistance. To dissect the cellular and molecular mechanisms of HMA resistance we have analyzed 204 BM samples from MDS patients at different stages of the disease who were enrolled in clinical trials of HMA therapy. Our preliminary studies revealed that MDS can be further divided in two distinct biologic...

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MDS patients who are treated with hypomethylating agents (HMAs, the current standard of care for this disease) almost universally develop resistance to these drugs and subsequently progress to acute myeloid leukemia. Patients in whom the therapy has failed have dismal prognoses and poor complete response rates to standard therapy. Almost nothing is known about the mechanisms underlying HMA resistance. To dissect the cellular and molecular mechanisms of HMA resistance we have analyzed 204 BM samples from MDS patients at different stages of the disease who were enrolled in clinical trials of HMA therapy. Our preliminary studies revealed that MDS can be further divided in two distinct biological subgroups. In each MDS subtype, a different stem cell (HSC, the cell of origin in MDS) subpopulation expanded during progression subsequent to HMA failure. Molecular analysis of these HSC populations revealed that different molecular pathways underpin progressive disease in the two MDS subgroups and identified a list of potential druggable targets. In this proposal we will integrate basic and translational research with clinical trials to answer fundamental questions about our understanding of the stem cell that gives rise to the disease and is responsible for progression, while validating therapeutic targets against MDS. Results of this study will lead to the identification of prime targets to enlist into prognostic and drug discovery efforts to design novel therapeutic points of intervention. This project has the potential to accelerate the pace of MDS drug and therapeutic discovery which may eventually benefit patients with this incurable disease.

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