MICE BEARING A TARGETED INTERRUPTION OF THE HOMEOBOX GENE HOXA9 HAVE DEFECTS IN MYELOID, ERYTHROID, AND LYMPHOID HEMATOPOIESIS

Several homeobox genes of the HOXA and HOXB clusters are expressed in primitive blood cells, suggesting a role for HOX genes in normal hemat opoiesis. The HOXA9 gene is expressed in CD34(+) marrow cells and in d eveloping lymphocytes. We examined blood-forming organs of mice homozy gous for an interrupted HOXAS allele to determine if loss of HOX gene function is deleterious to hematopoiesis, HOXA9-/- mice have approxima tely 30% to 40% reductions in total leukocytes and lymphocytes (P <.00 1) and a blunted granulocytic response to granulocyte colony-stimulati ng factor (G-CSF), Homozygous mice have significantly smaller spleens and thymuses. Myeloid/erythroid and pre-B progenitors in the marrow ar e significantly reduced, but no significant decreases are noted in mix ed colonies, day 12 colony-forming units-spleen (CFU-S), or long-term culture-initiating cells (LTC-IC), suggesting little or no perturbatio n in earlier progenitors. Heterozygous animals display no hematopoieti c defects, The abnormalities in leukocyte production are transplantabl e, indicating that the defect resides in the hematopoietic cells, Thes e studies demonstrate a physiologic role for a HOX gene in blood cell differentiation, with the greatest apparent influence of HOXA9 at the level of the committed progenitor. (C) 1997 by The American Society of Hematology.