Stem cell-specific survival pathways drive the progression of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard-of-care for MDS patients is hypomethylating agent (HMA)-based therapy. However, the disease becomes resistant to this therapy and progresses to acute myeloid leukemia in almost half of patients. Patients in whom HMA-based therapy has failed have no approved second-line treatment options and a median survival duration of only 4-6 months.As cancer stem cells are the seeds of therapy failure and disease progression, we sought to understand MDS stem cells' biological properties to uncover vulnerabilities in the disease that could be therapeutically targeted to halt its evolution. Herein, we provide evidence that MDS stem cells in two distinct differentiation states are maintained over the clinical course of the disease and expand at progression. Mechanistically, we show that MDS progression relies on the recurrent activation of survival pathways that counteract the physiological mechanisms governing the maintenance and fate regulation of each stem cell differentiation state. The pharmacological inhibition of these pathways depletes MDS stem cells in co-culture systems and reduces tumor burden in patient-derived xenograft models. This study highlights the importance of exploiting stem cells' differentiation state specific vulnerabilities to develop targeted therapies to improve the treatment stratification and outcomes of patients in whom therapy has failed.