Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity.

Publication Type:

Journal Article

Source:

Cell stem cell, Volume 3, Issue 6, p.611-24 (2008)

Keywords:

2008, Animals, Antibody Development Core Facility, Cell Differentiation, Cell Lineage, Cell Proliferation, Cell Survival, Cells, Cultured, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Flow Cytometry Core Facility, Graft Survival, Granzymes, Hematopoiesis, hematopoietic stem cell transplantation, Hematopoietic Stem Cells, MICE, Mice, Knockout, Pancytopenia, Proto-Oncogene Proteins c-myc, Research Trials Office Core Facility - Biostatistics Service, Shared Resources, Signal Transduction, Stress, Physiological

Abstract:

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.