myelodysplastic syndrome progenitors Inhibition of overactivated p38 MAPK can restore hematopoiesis in

ABSTRACT The myelodysplastic syndromes (MDS) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias due to ineffective hematopoiesis. Development of effective treatments has been impeded by limited insights into any unifying pathogenic pathways. We provide evidence that the p38 MAP kinase is constitutively activated / phosphorylated in MDS bone marrows. Such activation is uniformly observed in varied morphologic subtypes of low risk MDS and correlates with enhanced apoptosis observed in MDS hematopoietic progenitors. Most importantly, pharmacological inhibition of p38α by a novel small molecule inhibitor, SCIO-469, decreases apoptosis in MDS CD34+ progenitors and leads to dose-dependant increases in erythroid and myeloid colony formation. Downregulation of the dominant p38isoform by siRNA also leads to enhancement of hematopoiesis in MDS bone α marrow progenitors in vitro . These data implicate p38 MAPK in the pathobiology of ineffective hematopoiesis in low risk MDS and provide a strong rationale for clinical investigation of SCIO-469 in MDS. From bloodjournal.hematologylibrary.org by guest on June 4, 2013. For personal use only.