ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival.
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...
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0312864&type=printable |
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| author | Joseph B An Karen S Hathcock Seth M Steinberg Hyoyoung M Choo-Wosoba Richard J Hodes |
| author_facet | Joseph B An Karen S Hathcock Seth M Steinberg Hyoyoung M Choo-Wosoba Richard J Hodes |
| author_sort | Joseph B An |
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| description | 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. |
| format | Article |
| id | doaj-art-8f00f2e247a34f24ac6d3e204cdfa22f |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-8f00f2e247a34f24ac6d3e204cdfa22f2025-08-20T02:38:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-011912e031286410.1371/journal.pone.0312864ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival.Joseph B AnKaren S HathcockSeth M SteinbergHyoyoung M Choo-WosobaRichard J HodesMice 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0312864&type=printable |
| spellingShingle | Joseph B An Karen S Hathcock Seth M Steinberg Hyoyoung M Choo-Wosoba Richard J Hodes ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival. PLoS ONE |
| title | ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival. |
| title_full | ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival. |
| title_fullStr | ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival. |
| title_full_unstemmed | ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival. |
| title_short | ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival. |
| title_sort | atm deficient murine thymic t cell lymphoblastic lymphomas are pten deficient and require akt signaling for survival |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0312864&type=printable |
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