USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia.
Animals
Carcinogenesis
/ genetics
Cell Proliferation
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Genetic Therapy
Humans
Jumonji Domain-Containing Histone Demethylases
/ genetics
Jurkat Cells
Leukemia, T-Cell
/ genetics
Mice
Receptor, Notch1
/ genetics
Signal Transduction
/ genetics
Ubiquitin-Specific Peptidase 7
/ genetics
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 01 2019
01 01 2019
Historique:
received:
05
06
2018
revised:
18
07
2018
accepted:
11
09
2018
pubmed:
19
9
2018
medline:
27
2
2020
entrez:
19
9
2018
Statut:
ppublish
Résumé
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models. We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.
Identifiants
pubmed: 30224337
pii: 1078-0432.CCR-18-1740
doi: 10.1158/1078-0432.CCR-18-1740
pmc: PMC6320313
mid: NIHMS1507350
doi:
Substances chimiques
NOTCH1 protein, human
0
Receptor, Notch1
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
KDM6B protein, human
EC 1.14.11.-
USP7 protein, human
EC 3.4.19.12
Ubiquitin-Specific Peptidase 7
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
222-239Subventions
Organisme : NCI NIH HHS
ID : R01 CA248770
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221848
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM108569
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States
Organisme : NHGRI NIH HHS
ID : R43 HG006634
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA080621
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM144295
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008152
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA188293
Pays : United States
Informations de copyright
©2018 American Association for Cancer Research.
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