USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia.
- Jin Q Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Martinez CA Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Arcipowski KM Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Zhu Y Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Gutierrez-Diaz BT Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Wang KK Master of Science in Biotechnology Graduate Program, Northwestern University, Evanston, Illinois.
- Johnson MR Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Volk AG Division of Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, Illinois.
- Wang F Progenra Inc., Malvern, Pennsylvania.
- Wu J Progenra Inc., Malvern, Pennsylvania.
- Grove C Progenra Inc., Malvern, Pennsylvania.
- Wang H Progenra Inc., Malvern, Pennsylvania.
- Sokirniy I Progenra Inc., Malvern, Pennsylvania.
- Thomas PM Proteomics Center of Excellence, Northwestern University, Evanston, Illinois.
- Goo YA Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Abshiru NA Proteomics Center of Excellence, Northwestern University, Evanston, Illinois.
- Hijiya N Ann & Robert H. Lurie Children's Hospital, Northwestern University, Chicago, Illinois.
- Peirs S Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
- Vandamme N Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
- Berx G Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
- Goosens S Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
- Marshall SA Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Rendleman EJ Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Takahashi YH Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Wang L Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Rawat R Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Bartom ET Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Collings CK Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Van Vlierberghe P Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
- Strikoudis A Department of Pathology, New York University, New York, New York.
- Kelly S Department of Pathology, New York University, New York, New York.
- Ueberheide B Department of Biochemistry and Molecular Pharmacology, New York University, New York, New York.
- Mantis C Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois.
- Kandela I Center for Developmental Therapeutics, Northwestern University, Evanston, Illinois.
- Bourquin JP University Children's Hospital, Division of Pediatric Oncology, University of Zurich, Switzerland.
- Bornhauser B University Children's Hospital, Division of Pediatric Oncology, University of Zurich, Switzerland.
- Serafin V Oncohematology Laboratory, Department of Woman's and Child's Health, University of Padova, Padova, Italy.
- Bresolin S Oncohematology Laboratory, Department of Woman's and Child's Health, University of Padova, Padova, Italy.
- Paganin M Oncohematology Laboratory, Department of Woman's and Child's Health, University of Padova, Padova, Italy.
- Accordi B Oncohematology Laboratory, Department of Woman's and Child's Health, University of Padova, Padova, Italy.
- Basso G Oncohematology Laboratory, Department of Woman's and Child's Health, University of Padova, Padova, Italy.
- Kelleher NL Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Weinstock J Progenra Inc., Malvern, Pennsylvania.
- Kumar S Progenra Inc., Malvern, Pennsylvania.
- Crispino JD Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Shilatifard A Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.
- Ntziachristos P Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois. Panos.ntz@northwestern.edu.
- 2018-09-19
Published in:
- Clinical cancer research : an official journal of the American Association for Cancer Research. - 2019
Animals
Carcinogenesis
Cell Proliferation
Gene Expression Regulation, Neoplastic
Genetic Therapy
Humans
Jumonji Domain-Containing Histone Demethylases
Jurkat Cells
Leukemia, T-Cell
Mice
Receptor, Notch1
Signal Transduction
Ubiquitin-Specific Peptidase 7
Xenograft Model Antitumor Assays
English
PURPOSE
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.
EXPERIMENTAL DESIGN
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.
RESULTS
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. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo.
CONCLUSIONS
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.
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.
EXPERIMENTAL DESIGN
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.
RESULTS
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. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo.
CONCLUSIONS
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1158/1078-0432.CCR-18-1740
- PMID 30224337
- Persistent URL
- https://sonar.ch/global/documents/11936
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