加拿大多伦多大学Tak W. Mak和加拿大大学健康网络Julie Leca研究组发现，IDH2和TET2突变协同调节卵泡辅助性T细胞（Tfh）与血管免疫母细胞性T细胞淋巴瘤（AITL）微环境相互作用。2023年2月2日出版的《癌细胞》发表了这项成果。

研究人员制备了一种由Idh2和Tet2突变驱动AITL的小鼠模型。恶性Tfh细胞具有异常的转录组和表观遗传程序，破坏TCR信号传导。携带Idh2和Tet2突变的肿瘤来源Tfh细胞显示出与生发中心B细胞的串扰改变，促进B细胞克隆扩增，同时减弱Fas-FasL的相互作用以及减少B细胞凋亡。Idh2突变肿瘤的浆细胞数目和血管生成也增加，这意味着Idh2突变与特异性AITL TME之间存在主要关系。该小鼠模型具有人IDH2突变诱导AITL的几个特征，为探索靶向AITL患者Tfh-TME串扰的治疗提供了理论基础。

据介绍，AITL是一种外周T细胞淋巴瘤，起源于滤泡辅助T细胞并具有独特的肿瘤微环境（TME）。IDH2和TET2突变经常在AITL中同时发生，但它们对肿瘤发生的作用知之甚少。

附：英文原文

Title: IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interactionwith the AITL microenvironment

Author: Julie Leca, Franois Lemonnier, Cem Meydan, Jonathan Foox, Samah El Ghamrasni, Diana-Laure Mboumba, Gordon S. Duncan, Jerome Fortin, Takashi Sakamoto, Chantal Tobin, Kelsey Hodgson, Jillian Haight, Logan K. Smith, Andrew J. Elia, Daniel Butler, Thorsten Berger, Laurence de Leval, Christopher E. Mason, Ari Melnick, Philippe Gaulard, Tak W. Mak

Issue&Volume: 2023-02-02

Abstract: Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T cell lymphoma that originates from T follicular helper (Tfh) cells and exhibits a prominent tumor microenvironment (TME). IDH2 and TET2 mutations co-occur frequently in AITL, but their contribution to tumorigenesis is poorly understood. We developed an AITL mouse model that is driven by Idh2 and Tet2 mutations. Malignant Tfh cells display aberrant transcriptomic and epigenetic programs that impair TCR signaling. Neoplastic Tfh cells bearing combined Idh2 and Tet2 mutations show altered cross-talk with germinal center B cells that promotes B cell clonal expansion while decreasing Fas-FasL interaction and reducing B cell apoptosis. The plasma cell count and angiogenesis are also increased in the Idh2-mutated tumors, implying a major relationship between Idh2 mutation and the characteristic AITL TME. Our mouse model recapitulates several features of human IDH2-mutated AITL and provides a rationale for exploring therapeutic targeting of Tfh-TME cross-talk for AITL patients.

DOI: 10.1016/j.ccell.2023.01.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00003-X