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Coordinate PI3K pathway and Bcl-2 family disruption in AML

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Microsoft Word - 100710.docx Oncotarget 2012; 3: Oncotarget, December, Vol.3, No 12 Coordinate PI3K pathway and Bcl-2 family disruption in AML Prithviraj Bose, Mohamed Rahmani, and Steven Grant The B-cell lymphoma-2 (Bcl-2) family of pro- and anti-apoptotic proteins controls the mitochondrial pathway of apoptosis. Their central role in mediating the final common pathway of apoptosis in response to internal and external stressors makes them attractive therapeutic targets in neoplastic cells, which are often “primed” for apoptosis. The major anti-apoptotic proteins are Bcl-2, Bcl-xL and myeloid cell leukemia-1 (Mcl-1). These promote cellular survival by sequestering pro-apoptotic proteins which function as apoptosis “sensitizers” (e.g., Bim, Bad) or “effectors” (Bax, Bak). Multiple studies have implicated Bcl-2 family proteins in AML pathogenesis, prognosis and resistance to chemotherapy. The discovery of the “BH3-mimetic” ABT-737, a specific inhibitor of the anti-apoptotic actions of Bcl-2 and Bcl-xL, demonstrated for the first time that specific protein-protein interactions could be disrupted using a small molecule [1]. Several groups [2, 3] have shown that Mcl-1, which is not inhibited by ABT-737, is the primary determinant of resistance to this agent. This, along with recent evidence that Mcl-1 may be more critical to the development and maintenance of AML than Bcl-2 or Bcl-xL [4], has prompted interest in combining agents that down-regulate Mcl-1 with ABT-737 in AML to simultaneously disable multiple arms of the mitochondrial apoptotic regulatory machinery. Thus, cyclin-dependent kinase inhibitors [3] and sorafenib [5] synergize with ABT-737 in pre-clinical studies of AML. The phosphatidylinositol-3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway is one of the most frequently dysregulated survival pathways in human malignancies, including AML, leadi

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