Proposed model of pathogenesis of stem cell apoptosis in MDS. A mutation in a stem cell compartment can give rise to a malignant clone. Interactions of the abnormal stem cell clones with the bone marrow microenvironment can lead to increased proinflammatory cytokine production in the bone marrow. Normal stem cell clones can undergo apoptosis, leading to ineffective hematopoiesis and low blood counts in early stage/low-grade MDS. Elimination of normal stem cells and clonal evolution of abnormal stem cell clones in late stages of MDS lead to development of leukemia. p38 MAPK inhibition can disrupt cytokine-driven apoptosis in low-grade MDS and potentially restore normal hematopoiesis. Apapted from Zhou et al with permission.¹