c-Myc is essential for hematopoietic stem cell differentiation and regulates Lin(-)Sca-1(+)c-Kit(-) cell generation through p21
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.
- SourceAvailable from: Przemyslaw Juszczynski
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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   . "
ABSTRACT: MYC is one of the most frequently deregulated oncogenes in human malignancies. It encodes a leucine zipper transcription factor that modulates a broad spectrum of cellular genes responsible for enhancing cell proliferation, cellular metabolism, growth, angiogenesis, metastasis, genomic instability, stem cell self-renewal and reduced differentiation. MYC functions predominantly as an amplifier of expression of already active genes, potentiating the pre-existing transcriptional program, although it can also repress certain transcriptional targets. In mouse models, MYC induces lymphomas, but requires cooperation with other lesions, including inactivation of the p53 pathway, structural alterations of BCL2 family members, or increased PI3K activity. In human B-cell tumors, MYC rearrangements involving the 8q24 region and immunoglobulin heavy or light genes are a hallmark of Burkitt lymphoma (BL), but can also occur in other lymphoid malignancies, that include diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU), plasma cell myeloma (PCM), mantle cell lymphoma (MCL) and plasmablastic lymphoma. For non-BL lymphoid malignancies, MYC fusions represent secondary genetic events and exist in the context of complex karyotypes. Regardless of the mechanism deregulating MYC, lymphomas over-expressing MYC are addicted to this oncogene, highlighting the potential clinical utility of MYC targeting strategies. Several promising approaches for pharmaceutical intervention have been suggested which are now in preclinical or clinical development. Herein, we therefore review the molecular pathogenetic mechanisms associated with MYC deregulation in human B-cell lymphomas and their implications for therapies targeting MYC.Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 12/2014; 1846(2). DOI:10.1016/j.bbcan.2014.08.006 · 7.58 Impact Factor
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- "However, loss-of-function experiments suggest that the pathway is not essential . 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  . "
ABSTRACT: Adult stem cells reside in a specialized microenvironment, the niche, which controls their behavior. As mammary stem cells, and consequently their niches, are still poorly defined, we look at better-characterized adult mammalian stem cell niches in the hematopoietic system and the skin. We attempt to define the mammary stem cell niche functionally, based on the widely used mammary fat pad reconstitution assay. We note that the concept of the niche needs to be extended from the specialized microenvironment described in the hematopoietic system, to a model that takes into account the macroenviroment, as recently shown in the skin, and systemic clues as we will illustrate for the mammary gland where the reproductive hormones are major determinants of stem cell activation. In fact, in the mammary gland a special type of stem cells is determined only during pregnancy. Reproductive hormones act on hormone receptor positive cells, sensor cells, in the mammary epithelium to induce paracrine signaling that leads to activation of stem cells. Some of the downstream mediators are in common with other niches such as Wnt and possibly Notch signaling. Other signals are specific to the mammary gland such as amphiregulin and RANKL.Breast disease 02/2008; 29:69-82.