THE ROLE OF HOX HOMEOBOX GENES IN NORMAL AND LEUKEMIC HEMATOPOIESIS

A sizable amount of new data points to a role for the HOX family of ho meobox genes in hematopoiesis. Recent studies have demonstrated that H OXA and HOXB genes are expressed in human CD34(+) cells, and are downr egulated as cells leave the CD34(+) compartment. In addition, expressi on of certain genes, including HOXB3 and HOXB4, is largely restricted to the long-term culture-initiating cell enriched pool, containing the putative stem cell population, Studies have also shown that HOX genes appear to be important for normal T lymphocyte and activated natural killer cell function. Overexpression of Hox-b4 in transplanted murine marrow cells results in a dramatic expansion of stem cells, while main taining normal peripheral blood counts. In contrast, overexpression of Hox-a10 resulted in expansion of progenitor pools, accompanied by uni que changes in the differentiation patterns of committed progenitors, Overexpression of Hox-a10 or Hox-bs led to the development of myeloid leukemias, while animals transfected with marrow cells overexpressing Hox-b4 do not appear to develop malignancies, Blockade of HOX gene fun ction using antisense oligonucleotides has revealed that several HOX g enes appear to influence either myeloid or erythroid colony formation. Mice homozygous for a targeted disruption of the Hox-a9 gene show red uced numbers of granulocytes and lymphocytes, smaller spleens and thym uses, and reduced numbers of committed progenitors. These studies demo nstrate that HOX homeobox genes play a role in both the early stem cel l function as well as in later stages of hematopoietic differentiation , and that perturbations of HOX gene expression can be leukemogenic.