29 - Transcriptional Regulation of Hematopoietic Stem Cells

Abstract

This chapter illustrates how an understanding of transcriptional regulation within hematopoietic stem cells (HSCs) helps in understanding the mechanisms that specify HSC formation and the influence of transcriptional networks on HSC behavior. One of the fundamental issues facing current biology concerns the molecular mechanisms whereby, multipotent stem cells are formed and subsequently undergo tightly regulated differentiation to form multiple, distinct progeny. Hematopoiesis has served as a model process for studying stem cell biology, and a close developmental link between the formation of embryonic blood and the formation of endothelial cells has long been recognized. However, the transcriptional networks that control the formation and functioning of HSCs are still poorly understood. Several studies are consistent with the presence of bipotent hemangioblast cells in adult bone marrow. Moreover, multipotent adult progenitor cells have been described recently. Studies of other stem cell systems suggest that the environment surrounding HSCs, the so-called stem cell niche, is likely to provide cell–cell and cell–extracellular matrix interactions important for stem cell self-renewal. Two main concepts have been put forward to explain how HSCs undergo lineage commitment: first, there are instructive models in which HSCs respond to external stimuli, such as cytokines, cell–cell, and cell–extracellular matrix interactions; second, there are selective models in which lineage choice would be mostly random with the appropriate number of mature cells being controlled by external stimuli acting selectively on HSC progeny. The construction of regulatory gene networks is emerging as an important way of integrating expression, regulatory, and developmental information with the underlying genome sequence, which contains the code controlling development. HSCs are the targets for transformation in many hematological malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia, the myelodysplastic syndromes, and the myeloproliferative disorders.