HoxA10 regulates transcription of the gene encoding transforming growth factor beta2 (TGFbeta2) in myeloid cells

HoxA10 is a homeodomain transcription factor that is maximally expressed in myeloid progenitor cells. HoxA10 is overexpressed in a poor prognosis subset of human acute myeloid leukemia (AML) and in vivo overexpression of HoxA10 in murine bone marrow induces myeloid leukemia. HoxA10 contributes to myeloid progenitor expansion and differentiation block, but few target genes have been identified that explain the influence of HoxA10 on these processes. The current study identifies the gene encoding transforming growth factor β2 (TGFβ2) as a HoxA10 target gene. We found that HoxA10 activated TGFβ2 transcription by interacting with tandem cis elements in the promoter. We also determined that HoxA10 overexpression in myeloid progenitor cells increased Tgfβ2 production by the cells. Tgfβ2 stimulates proliferation of hematopoietic stem and progenitor cells. Therefore, these studies identified autocrine stimulation of myeloid progenitors by Tgfβ2 as one mechanism by which HoxA10 expands this population. Because HoxA proteins had not been previously known to influence expression of pro-proliferative cytokines, this has implications for understanding molecular mechanisms involved in progenitor expansion and the pathobiology of AML.