Acute myeloid leukemia (AML) is a lethal disease which dramatically increases in incidence in individuals >65 years of age, the fastest growing population in the United States. Regrettably, the 5 year survival rate drops dramatically in patients over 65 years (4.3%) compared to patients less than 65 years (34.45%). These dismal statistics have led scientists to investigate the molecular mechanism(s) underlying the transforming process leading to AML in an effort to develop novel, molecularly-targeted, effective, and less toxic therapies for use in this lethal disease. Internal tandem duplications (ITD), an in-frame mutation leading to insertion or duplication of several amino acids near the juxtamembrane domain, in fms-like tyrosine kinase receptor (FLT3), are seen in nearly 25% of all AML patients and confer a poor prognosis. Expression of the Shp2 protein tyrosine phosphatase is consistently elevated in primary leukemia cell specimens from multiple adult acute leukemias compared to Shp2 levels in bone marrow mononuclear cells from healthy controls. However, how Shp2 contributes to myeloid leukemogenesis is unknown. We present preliminary studies demonstrating that Shp2 is constitutively associated with FLT3 in mutant N51-FLT3- and N73-FLT3-bearing cells and that genetic disruption of Shp2 and pharmacologic inhibition of Shp2 preferentially reduces N51-FLT3-induced hyperproliferation compared to that observed in WT FLT3-bearing cells. As a corollary, since Shp2 has been shown to regulate the activation of the Rac subfamily of Rho-GTPases in hematopoietic cells, we predicted that Rac1 and/or Rac2 may also be relevant effectors of FLT3-ITDs. Consistently, we present preliminary findings demonstrating that pharmacologic Rac inhibition using NSC23766 or genetic disruption of Rac2 results in significantly reduced N51-FLT3-induced hyperproliferation. Based on our preliminary data, the central role of STAT5 hyperactivation in FLT3-ITD-induced leukemia, and the reported positive roles of Shp2 and Rac1/Rac2 promoting activated STAT5 nuclear accumulation, the central hypothesis of this application is that, mechanistically, Shp2 and Rac1/Rac2 contribute to FLT3-ITD-induced leukemia by facilitating STAT5 nuclear localization and the expression of STAT5-responsive pro-leukemogenic genes. The objectives of this application are to define the consequences of genetic disruption of Shp2 and Rac1/Rac2 on the activation and nuclear localization of STAT5 and on the development of FLT3-ITD-induced myeloproliferative disorder (MPD) in vivo, to examine the efficacy of a Shp2 inhibitor and a Rac1 inhibitor in an AML xenograft model in vivo, and to define the intracellular tyrosines within the juxtamembrane and the duplicated juxtamembrane of FLT3-ITD that contribute to ligand-independent proliferation.
Acute myeloid leukemia (AML) is a lethal disease which dramatically increases in incidence in individuals >65 years of age, the fastest growing population in the United States. We present studies that will examine the role of the protein tyrosine phosphatase, Shp2, and the Rac subfamily of Rho GTPases in the pathogenesis of AMLs bearing internal tandem duplications (ITDs) of the fms-like tyrosine kinase receptor (FLT3). Results from these studies are expected to identify new therapeutic targets for treating AML.
|Pandey, Ruchi; Saxena, Mallika; Kapur, Reuben (2017) Role of SHP2 in hematopoiesis and leukemogenesis. Curr Opin Hematol 24:307-313|
|Ghosh, Joydeep; Kapur, Reuben (2017) Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia. Exp Hematol 50:13-21|
|Liu, W; Yu, W-M; Zhang, J et al. (2017) Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. Leukemia 31:1415-1422|
|Ghosh, Joydeep; Kobayashi, Michihiro; Ramdas, Baskar et al. (2016) S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance. J Clin Invest 126:2621-5|
|Richine, B M; Virts, E L; Bowling, J D et al. (2016) Syk kinase and Shp2 phosphatase inhibition cooperate to reduce FLT3-ITD-induced STAT5 activation and proliferation of acute myeloid leukemia. Leukemia 30:2094-2097|
|Garringer, Holly J; Irimia, Jose M; Li, Wei et al. (2016) Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy. PLoS One 11:e0161341|
|Li, Xing Jun; Deng, Lisa; Brandt, Stephanie L et al. (2016) Role of p85? in neutrophil extra- and intracellular reactive oxygen species generation. Oncotarget 7:23096-105|
|Kapur, Reuben; Shi, Jianjian; Ghosh, Joydeep et al. (2016) ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells. Oncotarget 7:16936-47|
|Li, Xing Jun; Goodwin, Charles B; Nabinger, Sarah C et al. (2015) Protein-tyrosine phosphatase Shp2 positively regulates macrophage oxidative burst. J Biol Chem 290:3894-909|
|Niemeyer, Charlotte M; Loh, Mignon L; Cseh, Annamaria et al. (2015) Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia. Haematologica 100:17-22|
Showing the most recent 10 out of 35 publications