The molecular basis of T-PLL is an actionable perturbation of TCL1/ATM- and epigenetically instructed damage responses

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. To address its incomplete molecular concept, we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identified novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM towards a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.EGA study EGAS00001002744

T细胞幼淋巴细胞白血病（T-cell prolymphocytic leukemia, T-PLL）是一种罕见且预后不良的成熟T细胞恶性肿瘤。为阐明其尚未完全明确的分子机制，我们整合了111例经过充分表征的患者的基因表达、等位基因拷贝数（allelic copy number, CN）以及核苷酸序列变异的大规模组学分析数据。除了显著的T细胞活化特征与普遍存在的克隆变异外，我们还鉴定出了拷贝数变异的新型热点区域、融合分子、可变剪接转录本以及与疾病进展相关的动态变化。T-PLL的整体病变谱主要可归类为DNA损伤应答、T细胞受体/细胞因子信号通路以及组蛋白调控这三类核心信号轴。我们构建了T-PLL发病机制的多维模型，其核心为TCL1过表达与ATM功能损伤性变异作为起始核心病变的独特组合。TCL1介导的生物学效应与功能受损的ATM协同作用，最终形成DNA损伤处理能力受损的致白血病表型。功能异常的ATM无法有效缓解升高的氧化应激负荷与端粒磨损，也无法激活p53依赖的细胞凋亡应答以应对基因毒性损伤。作为非基因毒性治疗策略，p53激活剂与组蛋白去乙酰化酶抑制剂的协同组合可恢复此类细胞死亡程序的执行。EGA研究EGAS00001002744