Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by poor prognosis. While incremental improvements in chemotherapy regimens have been described for AML treatment in recent years;majority of AML patients relapse and a significant number of them die of this disease. Although the precise mechanism(s) leading to relapse are poorly understood, lack of elimination of leukemia stem cells (LSCs) and the acquisition of drug resistance mutations such as those found in patients with FLT3 receptor may be some of the significant contributors. Internal tandem duplications (ITD) in FLT3 are observed in nearly 30% of all AML patients and confer poor prognosis. Likewise, KIT activation loop mutations (e.g. KITD816V), that are resistant to Gleevec, are exclusively associated with ~ 50% of core binding factor (CBF)-AMLs and 95% of systemic mastocytosis (SM) patients (a form of myeloproliferative neoplasm (MPN)) and confer poor overall survival. While several clinical trials have been conducted utilizing FLT3 and KIT inhibitors for above indications, none have shown significant long-term clinical efficacy. Thus, fo the elderly, who demonstrate the highest incidence of and mortality from these diseases, continued investigation for novel molecularly-targeted and less toxic therapies are desperately needed. Recently, four independent clinical studies comprising of 157 AML patients demonstrated overexpression of focal adhesion kinase (FAK) in up to 50% of patient derived BM cells but not in normal cells. In a significant number of these patients, FAK was hyper-phosphorylated on Y397, a critical residue for its activation. FAK+ AML cells displayed significantly higher migration and resistance to daunorubicin compared with FAK- cells and FAK expression significantly correlated with high blast cell counts, early death and shorter survival rate. In addition to FAK, a recent study utilizing 112 AML patients also showed that expression of phosphorylated (p) pStat5 in newly diagnosed AML patients is associated with poor overall survival. Remarkably, constitutive activation of pStat5 was seen in 100% of mastocytosis patients bearing the KITD816V mutation. Importantly, a strong correlation between the presence of pStat5 and FLT3ITD mutations was observed in AML patients. These clinical findings suggest that FLT3ITD/KITD814V, FAK and Stat5 are likely to contribute to the development of AML and MPNs;however, the relationship between these signaling molecules in the development or progression of AML or MPNs is poorly understood. Importantly, although Stat5 has been implicated in several hematologic malignancies involving LSCs;how precisely activation of Stat5 is regulated in the cytoplasm or in the nucleus and what are the signaling molecules involved in its nuclear import in the context of AML or MPN remains an enigma. We will define the role of FAK and its downstream effectors including PAK1 and Stat5 in regulating FLT3ITD/KITD814V induced transformation. We hypothesize that hyper-activation of FAK via FLT3ITD/KITD814V and downstream phosphorylation and nuclear translocation of Stat5 in a PAK1 dependent manner contributes to FLT3ITD/KITD814V driven AML.

Public Health Relevance

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 a novel pathway involving FAK and PAK 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA173852-01A1
Application #
8639010
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Mufson, R Allan
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Bessler, Waylan K; Kim, Grace; Hudson, Farlyn Z et al. (2016) Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation. Hum Mol Genet 25:1129-39
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
Gao, Rui; Chen, Sisi; Kobayashi, Michihiro et al. (2015) Bmi1 promotes erythroid development through regulating ribosome biogenesis. Stem Cells 33:925-38
Pandey, Ruchi; Kapur, Reuben (2015) Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms. Mol Cancer 14:118
Zhang, Jilu; Ramadan, Abdulraouf M; Griesenauer, Brad et al. (2015) ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. Sci Transl Med 7:308ra160
Mantel, Charlie R; O'Leary, Heather A; Chitteti, Brahmananda R et al. (2015) Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell 161:1553-65
Chatterjee, Anindya; Ghosh, Joydeep; Kapur, Reuben (2015) Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder. Oncotarget 6:18250-64
Onishi, Chie; Mori-Kimachi, Satomi; Hirade, Tomohiro et al. (2015) Internal tandem duplication mutations in FLT3 gene augment chemotaxis to Cxcl12 protein by blocking the down-regulation of Rho-associated kinase via the Cxcl12/Cxcr4 signaling axis. J Biol Chem 290:28356
Kumar, Sachin; Xu, Juying; Kumar, Rupali Sani et al. (2014) The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation. J Exp Med 211:1741-58

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