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  • PMID: 23292005 was deleted because it is a duplicate of PMID: 23359317
Blood Cancer J. 2013 Jan;3(1):e99. doi: 10.1038/bcj.2012.44. Epub 2013 Jan 4.

The role of tumor suppressor p15Ink4b in the regulation of hematopoietic progenitor cell fate.

Author information

1
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.

Abstract

Epigenetic silencing of the tumor suppressor gene p15Ink4b (CDKN2B) is a frequent event in blood disorders like acute myeloid leukemia and myelodysplastic syndromes. The molecular function of p15Ink4b in hematopoietic differentiation still remains to be elucidated. Our previous study demonstrated that loss of p15Ink4b in mice results in skewing of the differentiation pattern of the common myeloid progenitor towards the myeloid lineage. Here, we investigated a function of p15Ink4b tumor suppressor gene in driving erythroid lineage commitment in hematopoietic progenitors. It was found that p15Ink4b is expressed more highly in committed megakaryocyte-erythroid progenitors than granulocyte-macrophage progenitors. More importantly, mice lacking p15Ink4b have lower numbers of primitive red cell progenitors and a severely impaired response to 5-fluorouracil- and phenylhydrazine-induced hematopoietic stress. Introduction of p15Ink4b into multipotential progenitors produced changes at the molecular level, including activation of mitogen-activated protein kinase\extracellular signal-regulated kinase (MEK/ERK) signaling, increase GATA-1, erythropoietin receptor (EpoR) and decrease Pu1, GATA-2 expression. These changes rendered cells more permissive to erythroid commitment and less permissive to myeloid commitment, as demonstrated by an increase in early burst-forming unit-erythroid formation with concomitant decrease in myeloid colonies. Our results indicate that p15Ink4b functions in hematopoiesis, by maintaining proper lineage commitment of progenitors and assisting in rapid red blood cells replenishment following stress.

KEYWORDS:

cell fate; differentiation; erythropoiesis; hematopoiesis; p15Ink4b; stem cell

PMID:
23359317
PMCID:
PMC3556574
DOI:
10.1038/bcj.2012.44

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