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.
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.
|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|
|Sharma, Namit; Everingham, Stephanie; Zeng, Li-Fan et al. (2014) Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 phosphatase for disease progression in mice. Oncotarget 5:6130-41|
|Zeng, Li-Fan; Zhang, Ruo-Yu; Yu, Zhi-Hong et al. (2014) Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J Med Chem 57:6594-609|