Laurenti, ElisaVarnum-Finney, BarbaraWilson, AnneFerrero, IsabelBlanco-Bose, William E.Ehninger, ArminKnoepfler, Paul S.Cheng, Pei-FengMacDonald, H. RobsonEisenman, Robert N.Bernstein, Irwin D.Trumpp, Andreas2010-11-302010-11-302010-11-30200810.1016/j.stem.2008.09.005https://infoscience.epfl.ch/handle/20.500.14299/60773WOS:000261670900010Myc activity is emerging as a key element in acquisition and maintenance of stem cell properties. We have previously shown that c-Myc deficiency results in accumulation of defective hematopoietic stem cells (HSCs) due to niche-dependent differentiation defects. Here we report that immature HSCs coexpress c-myc and N-myc mRNA at similar levels. Although conditional deletion of N-myc in the bone marrow does not affect hematopoiesis, combined deficiency of c-Myc and N-Myc (dKO) results in pancytopenia and rapid lethality. Interestingly, proliferation of HSCs depends on both myc genes during homeostasis, but is c-Myc/N-Myc independent during bone marrow repair after injury. Strikingly, while most dKO hematopoietic cells undergo apoptosis, only self-renewing HSCs accumulate the cytotoxic molecule GranzymeB, normally employed by the innate immune system, thereby revealing an unexpected mechanism of stem cell apoptosis. Collectively, Myc activity (c-Myc and N-Myc) controls crucial aspects of HSC function including proliferation, differentiation, and survival.Serine-Protease Inhibitor-6Granzyme-BProgenitor CellsSelf-RenewalDifferentiationGeneProliferationActivationExpressionFamilytext::journal::journal article::research article