PI3K Isoform Dependence and Translational Regulation of c-MYC in PTEN-Deficient Leukemia

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a lethal decrease that is usually caused by hyper-activation of PI3K signaling, generally featured with loss of Pten. In this thesis, using genetically engineered murine model of T-ALL initiated by Pten-loss, we studied the roles of different PI3K catalytic subunit isoforms in T cell specific PTEN null induced T-ALL. We show that neither \(p110\alpha\) nor \(p110\beta\) isoform is critical for the maintenance of the T cell specific PTEN loss induced T-ALL, suggesting potential critical role of the PI3K \(p110\delta\) and \(p110\gamma\) in PTEN-null induced T-ALL. Highly elevated c-MYC oncoprotein abundance is found in most cases of T-cell acute lymphoblastic leukemia (T-ALL) and plays a key pathogenic role in this disease. Notably, the co-occurrence of c-MYC overexpression and PTEN-deficiency is common in T-cell acute lymphoblastic leukemia (T-ALL). However, the mechanistic link between the two events resulting in this correlation has remained unclear and unexploited therapeutically. Using the genetically engineered murine model of T-ALL initiated by Pten-loss and featuring spontaneous overexpression of c-MYC as well as a panel of PTEN-deficient c-MYC-high human T-ALL cell lines, we found that the abundance of c-MYC in these cells is critically dependent on hyper-activation of PI3K-mTOR-S6K1 signaling. While multiple mechanisms have been proposed to allow PI3K signaling to regulate c-MYC expression, we found that the details of c-MYC regulation in T-ALL are unique, not occurring via the regulation of c-MYC stability by phosphorylation or the common translational initiation machinery via eIF4E. We demonstrate that the PI3K signaling pathway robustly regulates translation of MYC via eIF4A, a eukaryotic translation initiation factor with intrinsic RNA helicase activity. Notably, eIF4A inhibition, either by RNA interference or via the pharmacological inhibitor hippuristanol, efficiently suppresses MYC translation and tumor cell proliferation via a mechanism specifically dependent on the 5'UTR of c-MYC. Our study establishes a novel eIF4A-dependent mechanism of MYC translation essential in T-ALL, and identifies eIF4A as a promising therapeutic target in c-MYC-dependent hematological malignancies.