Hematopoietic Stem Cell Function and Survival Depend on c-Myc and N-Myc Activity

被引:238
作者
Laurenti, Elisa [1 ]
Varnum-Finney, Barbara [3 ]
Wilson, Anne [4 ]
Ferrero, Isabel [4 ]
Blanco-Bose, William E. [1 ]
Ehninger, Armin [1 ]
Knoepfler, Paul S. [5 ]
Cheng, Pei-Feng [5 ]
MacDonald, H. Robson [4 ]
Eisenman, Robert N. [5 ]
Bernstein, Irwin D. [3 ]
Trumpp, Andreas [1 ,2 ]
机构
[1] Swiss Inst Expt Canc Res, ISREC, Ecole Polytech Fed Lausanne, Sch Life Sci, CH-1066 Epalinges, Switzerland
[2] DKFZ ZMBH Alliance, Div Cell Biol, D-69120 Heidelberg, Germany
[3] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA
[4] Univ Lausanne, Lausanne Branch, Ludwig Inst Canc Res Ltd, CH-1066 Epalinges, Switzerland
[5] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA
基金
欧盟第七框架计划; 瑞士国家科学基金会;
关键词
D O I
10.1016/j.stem.2008.09.005
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
引用
收藏
页码:611 / 624
页数:14
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