A preclinical model of peripheral T-cell lymphoma GATA3 reveals DNA damage response pathway vulnerability

Peripheral T-cell lymphoma (PTCL) represents a rare group of heterogenous diseases in urgent need of effective treatments. A scarcity of disease-relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal-center B-cell hyperplasia model (Cγ1-Cre Blimp1fl/fl) through immune-competent mice. Lymphoma cells were identified as clonal TCRβ+ T-helper cells expressing T-follicular helper markers. We also observed coincident B-cell activation and development a de novo B-cell lymphoma in the model, reminiscent of B-cell activation/lymphomagenesis found in human PTCL. Molecular profiling linked the mPTCL to the high-risk 'GATA3' subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway enrichment, hyper-activated MYC and genome instability. Exome sequencing identified a human-relevant oncogenic β-catenin mutation possibly involved in T-cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting ATR in the DNA damage response (DDR), a result corroborated in PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T-cell lymphomagenesis and proposes DDR inhibition as an effective and readily translatable therapy in PTCL.

外周T细胞淋巴瘤（Peripheral T-cell lymphoma, PTCL）是一类罕见的异质性疾病，目前亟需开发有效的治疗手段。相关临床前模型的匮乏阻碍了该领域的研究进展。本研究通过将来自生发中心B细胞增生模型（Cγ1-Cre Blimp1fl/fl）的淋巴瘤移植至免疫健全小鼠体内并进行连续传代，成功分离得到一株新型小鼠PTCL（mPTCL）。经鉴定，该淋巴瘤细胞为表达滤泡辅助T细胞标志物的克隆性TCRβ阳性辅助T细胞。本模型中同时观察到B细胞激活与新发B细胞淋巴瘤的发生，这重现了人类PTCL中所见的B细胞激活与淋巴瘤发生过程。分子谱分析将该mPTCL归类为PTCL的高危GATA3亚型，表现为GATA3与Th2基因表达上调、PI3K/mTOR通路富集、MYC过度激活以及基因组不稳定性。外显子测序鉴定出一处与人类疾病相关的致癌性β-连环蛋白突变，该突变可能参与T细胞淋巴瘤的发生过程。体内实验中，靶向DNA损伤应答（DNA damage response, DDR）通路中的ATR可获得持久的治疗应答，该结果在PTCL细胞系中得到了证实。本研究阐明了T细胞淋巴瘤发生的分子与免疫学驱动机制，并提出DDR抑制可作为PTCL一种有效且易于实现临床转化的治疗策略。