Several lines of evidence suggest that abnormal expression of the Abd HoxA transcription factors (HoxA7- 11) contributes to the pathogenesis of myeloid malignancy. First, overexpression of HoxA7-11 is common in human acute myeloid leukemia (AML) and murine leukemogenesis models. Second, forced overexpression of HoxA10 in murine bone marrow induces a myeloproliferative disorder which evolves to AML after several months. Although mechanisms by which HoxA10 induces myeloproliferation are unknown, our previous studies identified a mechanism by which HoxA10 impacts differentiation. We found that HoxA10 represses transcription of genes that contribute to the mature myeloid phenotype;such as genes encoding the phagocyte oxidase proteins gp91PHOX and p67PHOX. In undifferentiated myeloid cells, we found that HoxA10 is maintained in a non-tyrosine phosphorylated state by SHP1 and SHP2 protein tyrosine phosphatases. Various hematopoietic cytokines induce HoxA10 tyrosine-phosphorylation during myelopoiesis. Since tyrosine-phosphorylation decreases HoxAIO-binding the negative cis elements in these oxidase genes, HoxA10-mediated transcriptional repression is abolished as differentiation proceeds. Based on these results, we hypothesize that overexpressed-HoxA10 only induces AML in the presence of additional mutations in pathways which influence cytokine-induced HoxAIO-tyrosine-phosphorylation. Consistent with this, we find rapid development of AML in mice transplanted with bone marrow overexpressing a tyrosine- mutant form of HoxA10, or co-overexpressing HoxA10 and an activated form of SHP2. However, development of myeloproliferation is equivalent in these transplantation experiments. Therefore, we also hypothesize that HoxAIO-regulation of genes involved in myeloid progenitor proliferation and survival is independent of HoxA10-tyrosine-phosphorylation-state. Since such genes have not been previously identified, we performed high through put screening and identified the genes encoding Cdx4, Meisl, Pbx2, the E3 ligase Triadl, Mkp2, programmed cell death protein 5, FGF2, Yaf2, and TGFp2 as potential HoxAIO- target-genes. Our hypotheses will be pursued through the following three specific aims:
Aim 1 : Identify HoxA10 target-genes involved in myeloproliferation and progenitor expansion.
Aim 2 : Determine mechanisms by which HoxA10 regulates transcription of such target genes.
Aim 3 : Determine the role of HoxA10 post-translational modification in regulation of these target genes and in leukemogenesis. Understanding mechanisms by which Hox proteins impact myeloid leukemogenesis involves identifying functionally significant Hox-target-genes. The goal of these studies is to determine the role of target-gene dysregulation in HoxA10-mediated leukemogenesis. Functionally significant target genes and the molecular pathways in which they are involved would be rational targets for therapeutic approaches to leukemia. Therefore, the goal of these studies is to identify novel targets for the treatment of myeloid malignancy.
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