Aberrant MYCN expression drives oncogenic hijacking of EZH2 as a transcriptional activator in peripheral T-cell lymphoma.

Autor:	Vanden Bempt M; Laboratory for Experimental Hematology, Department of Oncology, KU Leuven, Leuven, Belgium.; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Debackere K; Laboratory for Experimental Hematology, Department of Oncology, KU Leuven, Leuven, Belgium.; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Demeyer S; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Van Thillo Q; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Meeuws N; Laboratory for Experimental Hematology, Department of Oncology, KU Leuven, Leuven, Belgium.; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Prieto C; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Provost S; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Mentens N; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Jacobs K; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Gielen O; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Nittner D; Histopathology Expertise Center, VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Department of Oncology, KU Leuven, Leuven, Belgium., Ogawa S; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Kataoka K; Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.; Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan., Graux C; Department of Hematology, Mont-Godinne University Hospital, Yvoir, Belgium., Tousseyn T; Translational Cell & Tissue Research, KU Leuven, Leuven, Belgium.; Department of Pathology, University Hospital Leuven, Leuven, Belgium., Cools J; Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven, Leuven, Belgium.; VIB- Katholieke Universiteit Leuven Center for Cancer Biology, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium., Dierickx D; Laboratory for Experimental Hematology, Department of Oncology, KU Leuven, Leuven, Belgium.; Leuvens Kanker Instituut, KU Leuven-UZ Leuven, Leuven, Belgium.; Department of Hematology, University Hospital Leuven, Leuven, Belgium.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Dec 08; Vol. 140 (23), pp. 2463-2476.
DOI:	10.1182/blood.2022016428
Abstrakt:	Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of hematological cancers arising from the malignant transformation of mature T cells. In a cohort of 28 PTCL cases, we identified recurrent overexpression of MYCN, a member of the MYC family of oncogenic transcription factors. Approximately half of all PTCL cases was characterized by a MYC expression signature. Inducible expression of MYCN in lymphoid cells in a mouse model caused T-cell lymphoma that recapitulated human PTCL with an MYC expression signature. Integration of mouse and human expression data identified EZH2 as a key downstream target of MYCN. Remarkably, EZH2 was found to be an essential cofactor for the transcriptional activation of the MYCN-driven gene expression program, which was independent of methyltransferase activity but dependent on phosphorylation by CDK1. MYCN-driven T-cell lymphoma was sensitive to EZH2 degradation or CDK1 inhibition, which displayed synergy with US Food and Drug Administration-approved histone deacetylase (HDAC) inhibitors. (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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