IDH2和TET2突变协同调节T支持细胞与AITL微环境的功能相互作用。
IDH2 and TET2 mutations synergize to modulate T Follicular Helper cell functional interaction with the AITL microenvironment.
发表日期：2023 Feb 13
作者：
Julie Leca, Franҫois 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
来源：
CANCER CELL
摘要：
Angioimmunoblastic T细胞淋巴瘤（AITL）是源自T毛囊辅助细胞（Tfh）的外周T细胞淋巴瘤，具有突出的肿瘤微环境（TME）。在AITL中，IDH2和TET2突变经常共存，但它们对肿瘤发生的贡献尚不清楚。我们开发了一个AITL小鼠模型，该模型由Idh2和Tet2突变驱动。恶性Tfh细胞显示异常的转录组和表观遗传学程序，破坏了TCR信号传导。携带Idh2和Tet2突变的肿瘤性Tfh细胞表现出与生发中心B细胞的交互作用发生改变，促进B细胞克隆扩张，同时减少了Fas-FasL相互作用，并降低了B细胞凋亡。在Idh2突变的肿瘤中，浆细胞计数和血管生成也增加，暗示着Idh2突变与AITL TME的特征之间存在重要关系。我们的小鼠模型重现了人类IDH2突变的AITL的几个特征，并为探索针对Tfh-TME交互作用进行治疗提供了理由。版权所有©2023作者。Elsevier公司发表，版权所有。
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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.