Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL
Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL
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DOI：
10.1038/s41467-017-02688-6
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发表时间：
2018-02-15
影响因子：
16.6
通讯作者：
Herling，M.
中科院分区：
文献类型：
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作者：
Schrader，A.;Crispatzu，G.;Herling，M.
T细胞幼淋巴细胞白血病（T-PLL）是一种罕见的和预后不良的成熟T细胞恶性肿瘤。在这里，我们整合了111名患者的基因表达、等位基因拷贝数（CN）和核苷酸序列改变的大规模分析数据。除了突出的T细胞活化和流行的克隆变异的签名，我们还确定了CN变异，融合分子，替代转录，和进展相关的动态的新热点。T-PLL的整体病变谱主要注释为DNA损伤反应、T细胞受体/细胞因子信号传导和组蛋白调节的轴。我们建立了一个T-PLL发病机制的多维模型，该模型以TCL 1过表达与破坏性ATM畸变作为起始核心病变的独特组合为中心。由TCL 1施加的作用与受损的ATM合作，朝向受损的DNA损伤处理的致白血病表型。功能失调的ATM似乎在减轻升高的氧化还原负担和端粒磨损以及引起对基因毒性损伤的p53依赖性凋亡反应方面效率低下。作为非遗传毒性策略，p53再激活剂和去乙酰化酶抑制剂的协同组合恢复这种细胞死亡执行。
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here 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 identify 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 ofTCL1overexpression with damagingATMaberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward 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.
表达TCL1的链球菌淋巴细胞的端粒酶活性，凋亡和细胞周期进程。
影响因子：
8.8
作者：
Gabellini, C;Antonelli, A;Petrinelli, P;Biroccio, A;Marcucci, L;Nigro, G;Russo, G;Zupi, G;Elli, R
通讯作者：
Elli, R