c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.
Wilson
Anne
A
Genetics and Stem Cell Laboratory, Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland.
Murphy
Mark J
MJ
Oskarsson
Thordur
T
Kaloulis
Konstantinos
K
Bettess
Michael D
MD
Oser
Gabriela M
GM
Pasche
Anne-Catherine
AC
Knabenhans
Christian
C
Macdonald
H Robson
HR
Trumpp
Andreas
A
D000740:Anemia / Q000209:etiology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D002470:Cell Survival; D005260:Female; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D019426:Integrases / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D015820:Cadherins; D016023:Integrins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C045073:Cre recombinase; D019426:Integrases