c-Myc is essential for hematopoietic stem cell differentiation and regulates Lin(-)Sca-1(+)c-Kit(-) cell generation through p21

Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Universidad Autónoma de Madrid, Madrid, Spain.
Experimental Hematology (Impact Factor: 2.81). 10/2007; 35(9):1333-43. DOI: 10.1016/j.exphem.2007.05.015
Source: PubMed

ABSTRACT The c-Myc protein is a member of the basic region/helix-loop-helix/leucine zipper (bHLHZip) transcription factor family, which is implicated in regulation of proliferation, differentiation, and apoptosis in multiple cell types. The aim of this study was to characterize the role of the proto-oncogene c-myc in hematopoietic stem cells (HSC) during postnatal development.
We have generated a conditional mouse model that allows us to inactivate c-myc in bone marrow (BM) in an inducible fashion.
We show that conditional inactivation of c-Myc in BM severely impairs HSC differentiation, leading to a striking decrease in the number of lymphoid and myeloid cells. c-Myc deletion in BM causes substantial accumulation of a Lin(-)Sca-1(+)c-Kit(-) cell population expressing high levels of the cell-cycle inhibitor p21, whose origin and function are otherwise poorly characterized. In vivo inactivation of p21 and c-Myc normalizes Lin(-)Sca-1(+)c-Kit(-) cell numbers and restores normal proliferation. The potential origin and function of these cells are discussed.
c-Myc plays a role in HSC maintenance and differentiation and might be regulating generation of Lin(-)Sca-1(+)c-Kit(-) through the cell-cycle regulator p21.

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    • "In mouse models Myc is essential for development of hematopoietic system where it fine-tunes the balance between self-renewal and differentiation of hematopoietic stem cells [7] [8] [9]. "
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    • "However, loss-of-function experiments suggest that the pathway is not essential [68]. Loss of the transcription factor c-myc in HSCs increases the expression of cell adhesion proteins in stromal cells that seemingly retain HSCs in an extended niche resulting in decreased HSC differentiation [5] [132]. "
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