Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity.
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 Granzyme B, 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.
Laurenti
Elisa
E
Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC, Swiss Institute for Experimental Cancer Research, School of Life Science, CH-1066 Epalinges, Switzerland.
Varnum-Finney
Barbara
B
Wilson
Anne
A
Ferrero
Isabel
I
Blanco-Bose
William E
WE
Ehninger
Armin
A
Knoepfler
Paul S
PS
Cheng
Pei-Feng
PF
MacDonald
H Robson
HR
Eisenman
Robert N
RN
Bernstein
Irwin D
ID
Trumpp
Andreas
A
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D006085:Graft Survival / Q000235:genetics; D053804:Granzymes / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010198:Pancytopenia / Q000235:genetics / Q000503:physiopathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D053804:Granzymes