TY - JOUR
T1 - Hematopoietic Stem Cell Function and Survival Depend on c-Myc and N-Myc Activity
AU - Laurenti, Elisa
AU - Varnum-Finney, Barbara
AU - Wilson, Anne
AU - Ferrero, Isabel
AU - Blanco-Bose, William E.
AU - Ehninger, Armin
AU - Knoepfler, Paul S
AU - Cheng, Pei Feng
AU - MacDonald, H. Robson
AU - Eisenman, Robert N.
AU - Bernstein, Irwin D.
AU - Trumpp, Andreas
PY - 2008/12/4
Y1 - 2008/12/4
N2 - Myc 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.
AB - Myc 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.
KW - STEMCELL
UR - http://www.scopus.com/inward/record.url?scp=56549084319&partnerID=8YFLogxK
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U2 - 10.1016/j.stem.2008.09.005
DO - 10.1016/j.stem.2008.09.005
M3 - Article
C2 - 19041778
AN - SCOPUS:56549084319
VL - 3
SP - 611
EP - 624
JO - Cell Stem Cell
JF - Cell Stem Cell
SN - 1934-5909
IS - 6
ER -