TP63融合驱动多复合增强子重构、淋巴瘤发生以及EZH2的依赖性。
TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.
发表日期：2023 Sep 20
作者：
Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla B Heavican-Foral, Elisa Mandato, Huiyun Liu, Geoffrey M Nelson, Lu Yang, Renee Chen, Katherine A Donovan, Marcus K Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit J Nirmal, Salvia Jain, Catharine Leahy, Kristen L Jones, Kristen E Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint, Lydie Debaize, Hojong Yoon, Paola Dal Cin, Wing C Chan, Shannan J Ho Sui, Samuel Y Ng, Andrew L Feldman, Steven M Horwitz, Karen Adelman, Eric S Fischer, Chun-Wei Chen, David M Weinstock, Myles Brown
来源：
Epigenetics & Chromatin
摘要：
肿瘤蛋白p63基因（TP63）参与的基因融合在多种T和B细胞淋巴瘤中发生，并预示着对患者预后不佳。TP63融合的功能和机制仍不清楚，淋巴瘤患者中携带TP63融合的治疗靶点尚不存在。在这里，我们展示了TP63融合是真正的癌基因，对于融合阳性淋巴瘤是必不可少的。表达TBL1XR1::TP63，最常见的TP63融合基因的转基因小鼠，发展出了多种复制人类T和B细胞淋巴瘤的淋巴瘤。在这里，我们发现TP63融合基因协调两个表观遗传修饰复合物的招募，即由N末端TP63融合伙伴调节的核受体共抑制蛋白（NCoR）-组蛋白去乙酰化酶3（HDAC3），以及由C末端TP63成分调节的赖氨酸甲基转移酶2D（KMT2D），这两者都对融合依赖的存活至关重要。TBL1XR1::TP63在增强子上的定位推动了一个独特的细胞状态，包括促进MYC和多能组重压复合物2（PRC2）成分EED和EZH2的上调。用治疗药物valemetostat抑制EZH2对于治疗转基因淋巴瘤小鼠模型、异种移植物和携带TP63融合的患者来源异种移植物都非常有效。一位携带TP63重排的淋巴瘤患者对valemetostat治疗迅速有效。总之，TP63融合基因将伴侣成分联系在一起，共同协调多个表观遗传复合物，从而对EZH2抑制剂呈现出治疗敏感性。
Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.