p38 MAP kinase regulates stem cell apoptosis in human hematopoietic failure.

Myelodysplastic syndromes (MDS) are clonal stem cell disorders that lead to ineffective hematopoiesis and are common causes of low blood counts in the elderly. The exact molecular mechanisms regulating increased stem apoptosis in these disorders are not well defined. p38 MAPK activation is important in regulating the growth inhibitory signals of TNF-alpha, TGF-beta and Interferons on human hematopoiesis. Our findings show that p38 MAPK is overactivated in myelodysplasia bone marrows and regulates hematopoietic stem cell apoptosis. Inhibition of p38 MAPK by genetic or pharmacologic means decreases apoptosis and stimulates in vitro hematopoiesis from primary MDS hematopoietic progenitors. These studies point to the potential efficacy of selective p38alpha inhibitor, SCIO-469, in human bone marrow failure.