Tumor suppressor p15Ink4b determines cell fate of hematopoietic progenitors: implications for development of human blood disorders

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CLIN/TRANS-12

* FARE Award Winner

Authors

• R. Humeniuk
• M. Rosu-Myles
• J. Fares
• J. Bies
• L. Wolff

Abstract

Red blood cells (RBCs) are a vital component of mammalian blood. The anemia due to the loss of RBC is a life threatening condition, often accompanying blood diseases such as leukemias and myelodysplastic syndromes (MDS). A striking 60-80% of these diseases have deleted or silenced expression of p15INK4B. An increased understanding of the factors that drive erythroid lineage commitment in progenitor cells is critical for developing new treatments for blood disorders. Previous examination of p15Ink4b knock-out mouse models, revealed skewing of hematopoietic progenitor differentiation towards myeloid lineage (granulocytes, macrophages). Here, we demonstrate a novel function for p15Ink4b in driving commitment to the erythroid lineage. Mice lacking p15Ink4b have lower numbers of primitive RBC progenitors and died shortly after induction of hemolytic anemia by phenylhydrazine injection. Expression of p15Ink4b in blood progenitors induced dynamic changes at the molecular level that rendered multi-lineage cells more permissive to erythroid commitment and less permissive to myeloid commitment. In summary, we have defined a framework that determines how multipotent progenitors coordinate the balance between myeloid and erythroid differentiation. Central to this activity is p15Ink4b, which promotes erythroid fate while suppressing myeloid cell formation, a function that is particularly important in rapid RBC replenishment following stress.

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