Hypomorphic mTOR Downregulates CDK6 and Delays Thymic Pre-T LBL Tumorigenesis.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
05
07
2019
revised:
14
01
2020
accepted:
13
07
2020
pubmed:
5
8
2020
medline:
7
8
2021
entrez:
5
8
2020
Statut:
ppublish
Résumé
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 G
Identifiants
pubmed: 32747423
pii: 1535-7163.MCT-19-0671
doi: 10.1158/1535-7163.MCT-19-0671
pmc: PMC9574474
mid: NIHMS1613877
doi:
Substances chimiques
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2221-2232Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC011064
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 BC010008
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA077429
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010008
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011065
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006927
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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