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

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 a 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 co-factor 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 FDA-approved HDAC inhibitors. 3' end RNA sequencing data of murine MYCN-driven T cell lymphoma, and CD4 T cells (control).

外周T细胞淋巴瘤（Peripheral T cell lymphoma, PTCL）是一组起源于成熟T细胞恶性转化的异质性血液系统恶性肿瘤。在纳入28例PTCL病例的队列中，我们发现MYCN（MYC家族致癌转录因子成员）存在高频过表达。约半数PTCL病例表现出MYC表达特征。在小鼠模型的淋巴样细胞中诱导表达MYCN，可诱发T细胞淋巴瘤，该模型能够重现携带MYC表达特征的人类PTCL表型。整合小鼠与人类的表达谱数据，我们鉴定出EZH2是MYCN的关键下游靶标。值得注意的是，EZH2是MYCN介导的基因表达程序转录激活所必需的辅助因子，这一过程不依赖其甲基转移酶活性，但依赖CDK1介导的磷酸化。MYCN介导的T细胞淋巴瘤对EZH2降解或CDK1抑制敏感，且该疗法与FDA获批的组蛋白去乙酰化酶（HDAC）抑制剂具有协同作用。本数据集包含小鼠MYCN介导的T细胞淋巴瘤与CD4阳性T细胞（对照组）的3'端RNA测序数据。