Hematopoiesis is the process by which blood cells of multiple distinct lineages are produced throughout life. It has been estimated that about 1 trillion mature blood cells are produced in an adult human every day, including 200 billion erythrocytes and 60 billion neutrophilic leukocytes. The ultimate burden of the life-long production of these mature elements is carried out by a small population of primitive cells, termed hematopoietic stem cells (HSC), that reside predominantly in the bone marrow and have the capacity for multilineage differentiation and self-renewal divisions (i.e., they are self-maintaining). Candidate or known players controlling HSC properties range from molecules—such as growth factor receptors, adhesion molecules, and signal transduction molecules that enable communication with the external environment—to transcription factors and determinants of chromosome structure that ultimately dictate the changing repertoire of genes accessible and utilized by primitive hematopoietic cells in carrying out proliferative and differentiation decisions. Accumulating evidence from a number of recent studies (reviewed in ref. 92) points to transcription factors such as SCL/tal-1, Ikaros, AML-1, and GATA-2, to name but a few, as key components of the intrinsic processes involved in lineage determination and the subsequent lineage-specific differentiation of early hematopoietic cells. Among transcription regulators is the Hox homeobox family of genes, initially described in the fruit fly as genetic elements essential for specification of cell identity and pattern formation of a number of embryonic structures. Strikingly, Hox gene functions have been found to apply to most, if not all, multicellular organisms, albeit with very different end results, reflecting the “flexibility” of Hox genes in orchestrating tissue specification. This article is a review of emerging evidence linking members of this family and, likely, a larger Hox regulatory network to the control of HSC properties, early hematopoietic differentiation, and leukemogenesis. Additional coverage of this topic also can be found in a number of early and recent reviews.50, 52, 60, 85, 92
