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 hematopoiesis. The HOXA9 gene is expressed in CD34+ marrow cells and in developing lymphocytes. We examined blood-forming organs of mice homozygous for an interrupted HOXA9 allele to determine if loss of HOX gene function is deleterious to hematopoiesis. HOXA9-/- mice have approximately 30% to 40% reductions in total leukocytes and lymphocytes (P < .001) and a blunted granulocytic response to granulocyte colony-stimulating factor (G-CSF). Homozygous mice have significantly smaller spleens and thymuses. Myeloid/erythroid and pre-B progenitors in the marrow are significantly reduced, but no significant decreases are noted in mixed colonies, day 12 colony-forming units-spleen (CFU-S), or long-term culture-initiating cells (LTC-IC), suggesting little or no perturbation in earlier progenitors. Heterozygous animals display no hematopoietic defects. The abnormalities in leukocyte production are transplantable, indicating that the defect resides in the hematopoietic cells. These 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.
Lawrence
H J
HJ
Department of Medicine, University of California, San Francisco 94121, USA.
Helgason
C D
CD
Sauvageau
G
G
Fong
S
S
Izon
D J
DJ
Humphries
R K
RK
Largman
C
C
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D006098:Granulocytes; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology