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.
Blood. 2022 Dec 8;140(23):2463-2476. doi: 10.1182/blood.2022016428.
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.
外周 T 细胞淋巴瘤（PTCL）是一组异质性的血液系统恶性肿瘤，起源于成熟 T 细胞的恶性转化。在 28 例 PTCL 病例的队列中，我们发现 MYCN 的反复过度表达，MYCN 是致癌转录因子 MYC 家族的一员。大约一半的所有 PTCL 病例具有 MYC 表达特征。在小鼠模型中，淋巴样细胞中 MYCN 的诱导性表达导致 T 细胞淋巴瘤，其重现了具有 MYC 表达特征的人类 PTCL。整合小鼠和人类的表达数据，鉴定出 EZH2 是 MYCN 驱动的基因表达程序转录激活的关键下游靶标。值得注意的是，EZH2 被发现是 MYCN 驱动的基因表达程序转录激活的必需辅助因子，其独立于甲基转移酶活性，但依赖于 CDK1 的磷酸化。MYCN 驱动的 T 细胞淋巴瘤对 EZH2 降解或 CDK1 抑制敏感，这与美国食品和药物管理局批准的组蛋白去乙酰化酶（HDAC）抑制剂显示出协同作用。
