University Health Network, Princess Margaret Cancer Centre, Toronto, ON M5G 1L7, Canada.
University Paris-Est Créteil, INSERM U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France; AP-HP, Lymphoid Malignancies Unit, Henri Mondor Hospital, 94010 Créteil, France.
Cancer Cell. 2023 Feb 13;41(2):323-339.e10. doi: 10.1016/j.ccell.2023.01.003. Epub 2023 Feb 2.
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.
血管免疫母细胞性 T 细胞淋巴瘤 (AITL) 是一种外周 T 细胞淋巴瘤，起源于滤泡辅助性 T 细胞 (Tfh)，并表现出明显的肿瘤微环境 (TME)。IDH2 和 TET2 突变在 AITL 中经常同时发生，但它们对肿瘤发生的贡献尚不清楚。我们开发了一种由 Idh2 和 Tet2 突变驱动的 AITL 小鼠模型。恶性 Tfh 细胞表现出异常的转录组和表观遗传程序，损害 TCR 信号。携带 IDH2 和 TET2 突变的肿瘤性 Tfh 细胞与生发中心 B 细胞的异常相互作用促进了 B 细胞克隆扩增，同时降低了 Fas-FasL 相互作用，减少了 B 细胞凋亡。Idh2 突变瘤中的浆细胞计数和血管生成也增加，这意味着 Idh2 突变与 AITL 特征性 TME 之间存在重要关系。我们的小鼠模型再现了人类 IDH2 突变型 AITL 的几个特征，并为探索针对 Tfh-TME 相互作用的治疗靶向提供了依据，以治疗 AITL 患者。
