ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival

Abstract

Mice deficient in the ataxia telangiectasia mutated (ATM) kinase have impaired responses to genotoxic and oxidative stressors, predisposing them to develop thymic T-cell lymphoblastic lymphomas (T-LBL) resembling human T-cell acute lymphoblastic leukemias (T-ALL). A previous study identified genomic deletions of the gene encoding PTEN, a negative regulator of PI3K/AKT/mTOR signaling, in a subset of murine ATM-deficient (ATMKO) thymic T-LBLs; however, the frequency and consequences of these deletions were not defined. The present study demonstrates that the majority of established cultures of ATMKO T-LBLs isolated from ATMKO thymi have a variety of genomic Pten alterations and fail to express functional PTEN protein. In addition, all T-LBLs demonstrate constitutive expression of pAKT, indicating the presence of activated AKT signaling, and are sensitive to treatment with the pan-AKT inhibitor MK-2206, suggesting that these lymphomas are dependent on pAKT signaling for their survival. Lastly, ATM-deficiency itself does not cause loss of PTEN or dysregulated AKT signaling, as ATM-deficient non-malignant thymocytes express wild-type levels of PTEN and lack detectable pAKT. This study demonstrates for the first time that the majority of ATM-deficient thymic T-LBLs lose PTEN expression and all depend on AKT signaling for survival, suggesting their potential use as an animal model for PI3K/AKT/MTOR pathway dysfunction in human T-ALL.