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 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.