THE T-CELL ONCOGENIC PROTEIN HOX11 ACTIVATES ALDH1 EXPRESSION IN NIH 3T3 CELLS BUT REPRESSES ITS EXPRESSION IN MOUSE SPLEEN DEVELOPMENT

Hox11 is a homeobox gene essential for spleen formation in mice, since atrophy of the anlage of a developing spleen occurs in early embryoni c development in Hox11 null mice. HOX11 is also expressed in a subset of T-cell acute leukemias after specific chromosomal translocations. S ince the protein has a homeodomain and can activate transcription, it probably exerts at least some of its effects in vivo by regulation of target genes. Representational difference analysis has been used to is olate cDNA clones corresponding to mRNA species activated following st able expression of HOX11 in NIH 3T3 cells, The gene encoding the retin oic acid-synthesizing enzyme aldehyde dehydrogenase 1 (Aldh1), initial ly called Hdg-1, was found to be ectopically activated by HOX11 in thi s system. Study of Aldh1 gene expression during spleen development sho wed that the presence of Aldh1 mRNA inversely correlated with Hox11. H ox11 null mouse embryos have elevated Aldh1 mRNA in spleen primordia p rior to atrophy, while Aldh1 seems to be repressed by Hox11 during org anogenesis of the spleens of wild-type mice. This result suggests that expression of Aldh1 protein is negatively regulated by Hox11 and that abnormal expression of Aldh1 in Hox11 null mice may cause loss of spl enic precursor cells by aberrant retinoic acid metabolism.