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Molecular Cancer Therapeutics
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Models and Technologies

Hypomorphic mTOR Downregulates CDK6 and Delays Thymic Pre-T LBL Tumorigenesis

Joy M. Gary, John K. Simmons, Jinfei Xu, Shuling Zhang, Tyler J. Peat, Nicholas Watson, Benjamin J. Gamache, Ke Zhang, Alexander L. Kovalchuk, Aleksandra M. Michalowski, Jin-Qiu Chen, Tuddow Thaiwong, Matti Kiupel, Snehal Gaikwad, Maudeline Etienne, R. Mark Simpson, Wendy Dubois, Joseph R. Testa and Beverly A. Mock
Joy M. Gary
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
2Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
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John K. Simmons
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Jinfei Xu
3Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Shuling Zhang
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Tyler J. Peat
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Nicholas Watson
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Benjamin J. Gamache
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
4American University, Washington, DC.
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Ke Zhang
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Alexander L. Kovalchuk
5Laboratory of Immunogenetics, NIAID, NIH, Rockville, Maryland.
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Aleksandra M. Michalowski
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Jin-Qiu Chen
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Tuddow Thaiwong
2Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
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Matti Kiupel
2Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
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  • ORCID record for Matti Kiupel
Snehal Gaikwad
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Maudeline Etienne
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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R. Mark Simpson
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Wendy Dubois
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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Joseph R. Testa
3Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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  • For correspondence: mockb@mail.nih.gov joseph.testa@fccc.edu
Beverly A. Mock
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, Maryland.
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  • For correspondence: mockb@mail.nih.gov joseph.testa@fccc.edu
DOI: 10.1158/1535-7163.MCT-19-0671 Published October 2020
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Abstract

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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:2221–32

  • Received July 5, 2019.
  • Revision received January 14, 2020.
  • Accepted July 13, 2020.
  • Published first August 3, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (10)
October 2020
Volume 19, Issue 10
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Hypomorphic mTOR Downregulates CDK6 and Delays Thymic Pre-T LBL Tumorigenesis
Joy M. Gary, John K. Simmons, Jinfei Xu, Shuling Zhang, Tyler J. Peat, Nicholas Watson, Benjamin J. Gamache, Ke Zhang, Alexander L. Kovalchuk, Aleksandra M. Michalowski, Jin-Qiu Chen, Tuddow Thaiwong, Matti Kiupel, Snehal Gaikwad, Maudeline Etienne, R. Mark Simpson, Wendy Dubois, Joseph R. Testa and Beverly A. Mock
Mol Cancer Ther October 1 2020 (19) (10) 2221-2232; DOI: 10.1158/1535-7163.MCT-19-0671

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Hypomorphic mTOR Downregulates CDK6 and Delays Thymic Pre-T LBL Tumorigenesis
Joy M. Gary, John K. Simmons, Jinfei Xu, Shuling Zhang, Tyler J. Peat, Nicholas Watson, Benjamin J. Gamache, Ke Zhang, Alexander L. Kovalchuk, Aleksandra M. Michalowski, Jin-Qiu Chen, Tuddow Thaiwong, Matti Kiupel, Snehal Gaikwad, Maudeline Etienne, R. Mark Simpson, Wendy Dubois, Joseph R. Testa and Beverly A. Mock
Mol Cancer Ther October 1 2020 (19) (10) 2221-2232; DOI: 10.1158/1535-7163.MCT-19-0671
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