Hox regulation of normal and leukemic hematopoietic stem cells.

Herein we focus on recent studies of knock out mice that demonstrate a function for the clustered homeobox (Hox) genes in normal hematopoiesis, on papers that point to their general involvement in human leukemia, and discuss the advances in the understanding of the mechanisms underlying their role in these processes. Expression analysis and gain- or loss- of function studies have shown that Hox play an important role in the regulation of early stages of hematopoiesis, including the self-renewal of hematopoietic stem cells (HSCs)/early progenitors. In the area of leukemia, numerous models of murine leukemia have demonstrated a role for Hox in the pathobiology of the disease. Moreover, the identification of multiple Hox genes as partners of chromosomal translocations and the observed global deregulation of Hox genes and cofactors demonstrated by gene profiling of cells from leukemic patients, have unequivocally shown a major function for Hox genes and cofactors in a wide spectrum of human leukemia. The identification of Hox genes as HSC regulators has been exploited to develop strategies to efficiently expand HSCs ex vivo, a key step to the success of therapies based on HSC transplantation and the understanding of mechanisms underlying HSC regulation. As leukemia is the result of deregulation of normal HSC development, the elucidation of the role of Hox in the pathobiology of the disease is helping to understand how HSCs self-renew and differentiate, and moreover, should facilitate the development of strategies for the management of leukemia.