Mechanisms of PTEN inactivation and pAKT dependence in ATM-deficient thymic T cell lymphomas

Abstract

Abstract Ataxia telangiectasia mutated (ATM) is a serine-threonine kinase that is essential for maintaining genomic integrity in response to DNA double-strand breaks. AT patients and ATM-deficient mice develop lymphoid malignancies at high frequency, establishing ATM’s role as a tumor suppressor. It was previously reported that murine Atm−/− T cell lymphomas have a recurrent loss of the gene encoding phosphatase and tensin homolog (PTEN), a tumor suppressor that plays a critical role in inhibiting the PI3K/AKT/mTOR pathway. Our analyses of Atm−/− T cell lymphomas revealed that 12/13 express high levels of phospho-AKT (pAKT). This upregulation of AKT signaling is consistent with the finding that 11/12 pAKThigh tumors lack PTEN protein. One tumor was PTEN+ but failed to downregulate pAKT. Here, we study the Atm−/− tumor model in order to uncover the mechanism by which PTEN expression is ablated. Interestingly, our analyses found that 9/11 PTEN-deficient cell lines have incurred a variety of alterations including exonal deletions of pten or truncations of its mRNA, providing a basis for PTEN loss-of-function. The remaining three lines, however, possess full-length Pten exomes and transcripts. Sequencing the Pten mRNA of these cell lines is in progress to identify mechanisms responsible for the absence of PTEN protein. We have further observed that in vitro treatment of Atm−/− T cell lymphomas with the pAKT inhibitor MK2206 resulted in substantial impairment of survival, consistent with their dependence on activated AKT in the absence of regulation by PTEN. Taken together, these results demonstrate that the majority of Atm−/− T cell lymphomas lose PTEN function through multiple mechanisms and become dependent on AKT signaling for their survival.