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

The myelodysplastic syndromes (MDSs) are collections of heterogeneous hematologic diseases characterized by refractory cytopenlas as a result of 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 or 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, pharmacologic inhibition of p38 alpha 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. Down-regulation of the dominant p38 alpha isoform by siRNA also leads to enhancement of hematopolesis in MDS bone 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. (Blood. 2006;108:4170-4177) (c) 2006 by The American Society of Hematology.