Wiley interdisciplinary reviews. Systems biology and medicine
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Wiley Interdiscip Rev Syst Biol Med · Nov 2011
ReviewMechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies.
Hematopoiesis, the process by which all mature blood cells are generated from multipotent hematopoietic stem cells (HSCs), is a finely tuned balancing act in which HSCs must constantly decide between different cell fates: to proliferate, to self-renew or differentiate, to stay quiescent in the bone marrow niche or migrate to the periphery, to live or die. These fates are regulated by a complex interplay between cell-extrinsic cues and cell-intrinsic regulatory pathways whose function is to maintain a homeostatic balance between HSC self-renewal and life-long replenishment of lost blood cells. Improper regulation of these competing cellular programs can transform HSCs and progenitor cells into disease-initiating leukemic stem cells (LSCs). ⋯ In this review, we focus on recent developments in elucidating the regulatory networks governing normal HSC self-renewal programs and their implications for leukemic transformation. We describe the current technical and methodological limitations in isolating and characterizing HSCs and LSCs, and the emerging approaches that may afford a better understanding of the regulation of normal and leukemic hematopoiesis. Finally, we discuss how such basic mechanistic information may be of use for the design of novel therapies that will selectively reprogram and/or eliminate LSCs.