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Mechanisms controlling hematopoietic stem cell functions during normal hematopoiesis and hematological malignancies

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Abstract 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). Strikingly, many of the mechanisms required for maintenance of normal HSC fate decisions are equally critical for the aberrant functions of LSCs. Because of the inherent complexities of these molecular mechanisms, a systematic approach to understanding the regulatory networks underlying HSC self‐renewal is critical for uncovering the similarities and differences between HSCs and 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. WIREs Syst Biol Med 2011 3 681–701 DOI: 10.1002/wsbm.145 This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease Developmental Biology > Stem Cell Biology and Regeneration

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Hematopoietic cell differentiation is organized in a hierarchical fashion.

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Multiple signaling pathways from the niche are integrated in hematopoietic stem cell (HSC) to regulate self‐renewal.

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PI3‐kinase signaling pathway.

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Bmi1‐p53 cell intrinsic pathway.

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Leukemic stem cells (LSCs) may reside in distinct compartments and have both common and distinct features.

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