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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087717-10
Application #
8119565
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Welniak, Lisbeth A
Project Start
2001-04-01
Project End
2013-06-30
Budget Start
2011-08-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2011
Total Cost
$377,500
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Wang, Hao; Bei, Ling; Shah, Chirag A et al. (2015) HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1. J Immunol 194:5375-87
Bei, L; Shah, C; Wang, H et al. (2014) Regulation of CDX4 gene transcription by HoxA9, HoxA10, the Mll-Ell oncogene and Shp2 during leukemogenesis. Oncogenesis 3:e135
Shah, Chirag A; Bei, Ling; Wang, Hao et al. (2013) The leukemia-associated Mll-Ell oncoprotein induces fibroblast growth factor 2 (Fgf2)-dependent cytokine hypersensitivity in myeloid progenitor cells. J Biol Chem 288:32490-505
Bei, Ling; Shah, Chirag; Wang, Hao et al. (2012) ?-Catenin activates the HOXA10 and CDX4 genes in myeloid progenitor cells. J Biol Chem 287:39589-601
Shah, Chirag A; Bei, Ling; Wang, Hao et al. (2012) HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells. J Biol Chem 287:18230-48
Wang, Hao; Bei, Ling; Shah, Chirag A et al. (2011) HoxA10 influences protein ubiquitination by activating transcription of ARIH2, the gene encoding Triad1. J Biol Chem 286:16832-45
Shah, Chirag A; Wang, Hao; Bei, Ling et al. (2011) HoxA10 regulates transcription of the gene encoding transforming growth factor beta2 (TGFbeta2) in myeloid cells. J Biol Chem 286:3161-76
Bei, Ling; Huang, Weiqi; Wang, Hao et al. (2011) HoxA10 activates CDX4 transcription and Cdx4 activates HOXA10 transcription in myeloid cells. J Biol Chem 286:19047-64
Eklund, Elizabeth (2011) The role of Hox proteins in leukemogenesis: insights into key regulatory events in hematopoiesis. Crit Rev Oncog 16:65-76
Eklund, Elizabeth A (2010) Genomic analysis of acute myeloid leukemia: potential for new prognostic indicators. Curr Opin Hematol 17:75-8

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