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

•Transcriptomic analysis of PTCL tumors reveals recurrent MYCN overexpression and the presence of a MYC signature in 50% of PTCL cases.•EZH2 is a transcriptional cofactor for the MYCN-driven gene expression program, which confers sensitivity to HDAC inhibition. [Display omitted] Peripheral T-cell ly...

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Published in:Blood 2022-12, Vol.140 (23), p.2463-2476
Main Authors: Vanden Bempt, Marlies, Debackere, Koen, Demeyer, Sofie, Van Thillo, Quentin, Meeuws, Nienke, Prieto, Cristina, Provost, Sarah, Mentens, Nicole, Jacobs, Kris, Gielen, Olga, Nittner, David, Ogawa, Seishi, Kataoka, Keisuke, Graux, Carlos, Tousseyn, Thomas, Cools, Jan, Dierickx, Daan
Format: Article
Language:English
Subjects:
Enhancer of Zeste Homolog 2 Protein - genetics
Humans
Lymphoma, T-Cell, Peripheral - genetics
N-Myc Proto-Oncogene Protein - genetics
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Summary:•Transcriptomic analysis of PTCL tumors reveals recurrent MYCN overexpression and the presence of a MYC signature in 50% of PTCL cases.•EZH2 is a transcriptional cofactor for the MYCN-driven gene expression program, which confers sensitivity to HDAC inhibition. [Display omitted] 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. Peripheral T-cell lymphoma (PTCL) is a heterogeneous clinical entity with a dismal prognosis, suggesting a need to better understand its pathophysiology. Vanden Bempt and colleagues identified MYCN as a newly identified recurrent driver of PTCL through cooperation between MYCN and its downstream target EZH2, which depends on phosphorylation by CDK1. MYCN-driven PTCL is sensitive to EZH2 degradation or CDK1 inhibition and shows synergy with histone deacetylase inhibitors.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2022016428