{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:09:06Z","timestamp":1740146946042,"version":"3.37.3"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>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 <jats:italic>Pten<\/jats:italic> 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0312864","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T19:03:04Z","timestamp":1733425384000},"page":"e0312864","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival"],"prefix":"10.1371","volume":"19","author":[{"given":"Joseph B.","family":"An","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen S.","family":"Hathcock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seth M.","family":"Steinberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyoyoung M.","family":"Choo-Wosoba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.","family":"Hodes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"pone.0312864.ref001","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1126\/science.1192912","article-title":"ATM activation by oxidative stress.","volume":"330","author":"Z Guo","year":"2010","journal-title":"Science"},{"key":"pone.0312864.ref002","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1038\/nature02989","article-title":"Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells.","volume":"431","author":"K Ito","year":"2004","journal-title":"Nature"},{"key":"pone.0312864.ref003","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/sj.embor.7400210","article-title":"ATM and ataxia telangiectasia.","volume":"5","author":"PJ McKinnon","year":"2004","journal-title":"EMBO Rep"},{"key":"pone.0312864.ref004","article-title":"DNA damage sensing by the ATM and ATR kinases [Internet].","author":"A Marechal","year":"2013","journal-title":"5, Cold Spring Harb Perspect Biol."},{"key":"pone.0312864.ref005","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1136\/jcp.54.7.512","article-title":"Ataxia telangiectasia gene mutations in leukaemia and lymphoma.","volume":"54","author":"J. 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lymphomas"},{"key":"pone.0312864.ref012","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1084\/jem.20100285","article-title":"ATM-deficient thymic lymphoma is associated with aberrant tcrd rearrangement and gene amplification.","volume":"207","author":"S Zha","year":"2010","journal-title":"J Exp Med"},{"key":"pone.0312864.ref013","doi-asserted-by":"crossref","DOI":"10.1016\/S0092-8674(00)80086-0","article-title":"Atm-deficient mice: a paradigm of ataxia telangiectasia [Internet].","volume":"86","author":"C Barlow","year":"1996","journal-title":"Cell"},{"key":"pone.0312864.ref014","doi-asserted-by":"crossref","DOI":"10.1128\/MCB.22.9.3174-3177.2002","article-title":"RAG-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice [Internet].","volume":"22","author":"LK Petiniot","year":"2002","journal-title":"Molecular and cellular 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lymphoblastic leukemia (ALL); an MRC UKALL12\/ECOG 2993 study.","volume":"109","author":"AK Fielding","year":"2007","journal-title":"Blood"},{"key":"pone.0312864.ref024","first-page":"64","article-title":"Targeting PI3K\/Akt\/mTOR Signaling in Cancer.","author":"C Porta","year":"2014","journal-title":"4, Front Oncol."},{"key":"pone.0312864.ref025","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40591-015-0040-8","article-title":"Outlook on PI3K\/AKT\/mTOR inhibition in acute leukemia.","volume":"3","author":"L Fransecky","year":"2015","journal-title":"Mol Cell Ther"},{"key":"pone.0312864.ref026","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.tibs.2014.02.006","article-title":"PTEN function: the long and the short of it.","volume":"39","author":"BD Hopkins","year":"2014","journal-title":"Trends Biochem Sci"},{"key":"pone.0312864.ref027","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.3324\/haematol.2011.059030","article-title":"The 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Mavrakis","year":"2011","journal-title":"Nature genetics"},{"key":"pone.0312864.ref031","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.1172\/JCI34616","article-title":"PTEN posttranslational inactivation and hyperactivation of the PI3K\/Akt pathway sustain primary T cell leukemia viability.","volume":"118","author":"A Silva","year":"2008","journal-title":"J Clin Invest"},{"key":"pone.0312864.ref032","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/sj.leu.2405056","article-title":"T-cell lymphomas in T-cell-specific Pten-deficient mice originate in the thymus.","volume":"22","author":"TJ Hagenbeek","year":"2007","journal-title":"Leukemia"},{"issue":"12","key":"pone.0312864.ref033","doi-asserted-by":"crossref","first-page":"6664","DOI":"10.1073\/pnas.97.12.6664","article-title":"Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice.","volume":"97","author":"LK 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Chiang","year":"2009","journal-title":"The Journal of biological chemistry"},{"key":"pone.0312864.ref037","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrm3330","article-title":"The functions and regulation of the PTEN tumour suppressor.","volume":"13","author":"MS Song","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pone.0312864.ref038","article-title":"MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo [Internet].","volume":"9","author":"H Hiroshi","year":"2010","journal-title":"Molecular cancer therapeutics"},{"key":"pone.0312864.ref039","article-title":"The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia [Internet].","volume":"49","author":"Y Liu","year":"2017","journal-title":"Nature 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lymphoblastic leukaemia.","volume":"31","author":"M Tesio","year":"2017","journal-title":"Leukemia"},{"key":"pone.0312864.ref043","doi-asserted-by":"crossref","DOI":"10.1016\/j.molcel.2013.09.026","article-title":"Genome-wide consequences of deleting any single gene [Internet].","volume":"52","author":"X Teng","year":"2013","journal-title":"Molecular cell"},{"key":"pone.0312864.ref044","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20110105","article-title":"Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse [Internet].","volume":"208","author":"E Clappier","year":"2011","journal-title":"The Journal of experimental medicine"},{"key":"pone.0312864.ref045","doi-asserted-by":"crossref","DOI":"10.1038\/s41375-018-0046-8","article-title":"The subclonal complexity of STIL-TAL1+ T-cell acute lymphoblastic leukaemia [Internet].","volume":"32","author":"CL Furness","year":"2018","journal-title":"Leukemia"},{"key":"pone.0312864.ref046","doi-asserted-by":"crossref","DOI":"10.1182\/blood.2020006996","article-title":"Single-cell DNA amplicon sequencing reveals clonal heterogeneity and evolution in T-cell acute lymphoblastic leukemia [Internet].","volume":"137","author":"L Alberti-Servera","year":"2021","journal-title":"Blood"},{"key":"pone.0312864.ref047","doi-asserted-by":"crossref","DOI":"10.1158\/1078-0432.CCR-14-2888","article-title":"A Phase I\/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed\/Refractory Acute Lymphoblastic Leukemia [Internet].","volume":"21","author":"N Daver","year":"2015","journal-title":"Clinical cancer research: an official journal of the American Association for Cancer Research"},{"key":"pone.0312864.ref048","article-title":"Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma [Internet].","volume":"171","author":"Y Oki","year":"2015","journal-title":"British journal of haematology"},{"key":"pone.0312864.ref049","doi-asserted-by":"crossref","DOI":"10.1038\/leu.2012.136","article-title":"Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia [Internet].","volume":"26","author":"C Simioni","year":"2012","journal-title":"Leukemia"},{"key":"pone.0312864.ref050","doi-asserted-by":"crossref","DOI":"10.1016\/j.ccr.2013.10.022","article-title":"Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia [Internet].","volume":"24","author":"E Piovan","year":"2013","journal-title":"Cancer cell"},{"key":"pone.0312864.ref051","doi-asserted-by":"crossref","DOI":"10.1016\/j.lrr.2018.01.003","article-title":"1,25-OH2 vitamin D3 and AKT-inhibition increase glucocorticoid induced apoptosis in a model of T-cell acute lymphoblastic leukemia (ALL) [Internet].","volume":"9","author":"M Pistor","year":"2018","journal-title":"Leukemia research 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