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

Abstract

AbstractThe 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 Fancc−/− 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.