Distinct roles of stress-activated protein kinases in fanconi anemia type C deficient hematopoiesis

Abstract

The underlying molecular mechanisms that promote bone marrow failure in Fanconi anemia are incompletely understood. Evidence suggests that enhanced apoptosis of hematopoietic precursors is a major contributing factor. Previously, enhanced apoptosis of Fanconi anemia type C-deficient (Fancc -/-) progenitors was shown to involve aberrant p38 MAPK activation. Given the importance of c-Jun N-terminal kinase (JNK) in the stress response, we tested whether enhanced apoptosis of Fancct-/-cells also involved altered JNK activation. In Fancc -/- murine embryonic fibroblasts, tumor necrosis factor α (TNF-α) induced elevated JNK activity. In addition, JNK inhibition protected Fancc-/- murine embryonic fibroblasts and c-kit+ bone marrow cells from TNF-α-induced apoptosis. Importantly, hematopoietic progenitor assays demonstrated that JNK inhibition enhanced Fancc -/- colony formation in the presence of TNF-α. Competitive repopulation assays showed that Fancc-/- donor cells cultured with the JNK inhibitor had equivalent levels of donor chimerism compared with Fancc--/- donor cells cultured with vehicle control. In contrast, culturing Fancc-/- cells with a p38 MAPK inhibitor significantly increased repopulating ability, supporting an integral role of p38 MAPK in maintaining Fancc-/- hematopoietic stem cell function. Taken together, these data suggest that p38 MAPK, but not JNK, has a critical role in maintaining the engraftment of Fancc -/-reconstituting cells under conditions of stress. © 2009 by The American Society of Hematology.