Hypomorphic mTOR downregulates CDK6 and delays thymic Pre-T LBL tumorigenesis
| Autor: | Wendy Dubois, Benjamin J. Gamache, Beverly A. Mock, Shuling Zhang, Matti Kiupel, Snehal M. Gaikwad, John K. Simmons, Ke Zhang, Aleksandra M. Michalowski, Tuddow Thaiwong, Joy Gary, Nicholas Watson, Tyler J Peat, Jinfei Xu, Joseph R. Testa, Jinqiu-Qiu Chen, Maudeline Etienne, Alexander L. Kovalchuk, R. Mark Simpson |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Down-Regulation Mice Transgenic Palbociclib medicine.disease_cause Article 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Protein kinase B PI3K/AKT/mTOR pathway Gene knockdown Everolimus biology Chemistry Gene Expression Profiling TOR Serine-Threonine Kinases Cyclin-Dependent Kinase 6 medicine.disease Leukemia 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Cyclin-dependent kinase 6 medicine.drug |
| Zdroj: | Mol Cancer Ther |
| Popis: | PI3K/AKT/mTOR pathway hyperactivation is frequent in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). To model inhibition of mTOR, pre–T-cell lymphoblastic leukemia/lymphoma (pre-T LBL) tumor development was monitored in mice with T lymphocyte–specific, constitutively active AKT (Lck-MyrAkt2) that were either crossed to mTOR knockdown (KD) mice or treated with the mTOR inhibitor everolimus. Lck-MyrAkt2;mTOR KD mice lived significantly longer than Lck-MyrAkt2;mTOR wild-type (WT) mice, although both groups ultimately developed thymic pre-T LBL. An increase in survival was also observed when Lck-MyrAkt2;mTOR WT mice were treated for 8 weeks with everolimus. The transcriptional profiles of WT and KD thymic lymphomas were compared, and Ingenuity Pathway Upstream Regulator Analysis of differentially expressed genes in tumors from mTOR WT versus KD mice identified let-7 and miR-21 as potential regulatory genes. mTOR KD mice had higher levels of let-7a and miR-21 than mTOR WT mice, and rapamycin induced their expression in mTOR WT cells. CDK6 was one of the most downregulated targets of both let-7 and miR21 in mTOR KD tumors. CDK6 overexpression and decreased expression of let-7 in mTOR KD cells rescued a G1 arrest phenotype. Combined mTOR (rapamycin) and CDK4/6 (palbociclib) inhibition decreased tumor size and proliferation in tumor flank transplants, increased survival in an intravenous transplant model of disseminated leukemia compared with single agent treatment, and cooperatively decreased cell viability in human T-ALL/LBL cell lines. Thus, mTOR KD mice provide a model to explore drug combinations synergizing with mTOR inhibitors and can be used to identify downstream targets of inhibition. |
| Databáze: | OpenAIRE |
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