Braun Till, Dechow Annika, Friedrich Gregor, Seifert Michael, Stachelscheid Johanna, Herling Marco
Department I of Internal Medicine, Center for Integrated Oncology (CIO), Aachen-Bonn-Cologne-Duesseldorf, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne (UoC), Cologne, Germany.
Department of Hematology and Cellular Therapy, University of Leipzig, Leipzig, Germany.
Front Oncol. 2021 Nov 19;11:775363. doi: 10.3389/fonc.2021.775363. eCollection 2021.
T-cell prolymphocytic leukemia (T-PLL) is the most common mature T-cell leukemia. It is a typically aggressively growing and chemotherapy-resistant malignancy with a poor prognosis. T-PLL cells resemble activated, post-thymic T-lymphocytes with memory-type effector functions. Constitutive transcriptional activation of genes of the T-cell leukemia 1 (TCL1) family based on genomic inversions/translocations is recognized as a key event in T-PLL's pathogenesis. TCL1's multiple effector pathways include the enhancement of T-cell receptor (TCR) signals. New molecular dependencies around responses to DNA damage, including repair and apoptosis regulation, as well as alterations of cytokine and non-TCR activation signaling were identified as perturbed hallmark pathways within the past years. We currently witness these vulnerabilities to be interrogated in first pre-clinical concepts and initial clinical testing in relapsed/refractory T-PLL patients. We summarize here the current knowledge on the molecular understanding of T-PLL's pathobiology and critically assess the true translational progress around this to help appraisal by caregivers and patients. Overall, the contemporary concepts on T-PLL's pathobiology are condensed in a comprehensive mechanistic disease model and promising interventional strategies derived from it are highlighted.
T 细胞幼淋巴细胞白血病（T-PLL）是最常见的成熟 T 细胞白血病。它是一种典型的生长迅速且对化疗耐药的恶性肿瘤，预后较差。T-PLL 细胞类似于具有记忆型效应功能的活化胸腺后 T 淋巴细胞。基于基因组倒位/易位的 T 细胞白血病 1（TCL1）家族基因的组成性转录激活被认为是 T-PLL 发病机制中的关键事件。TCL1 的多种效应途径包括增强 T 细胞受体（TCR）信号。在过去几年中，围绕对 DNA 损伤的反应（包括修复和凋亡调节）的新分子依赖性，以及细胞因子和非 TCR 激活信号的改变被确定为受干扰的标志性途径。我们目前看到这些脆弱性在复发/难治性 T-PLL 患者的首个临床前概念和初步临床试验中受到探究。我们在此总结目前对 T-PLL 病理生物学分子理解的知识，并批判性地评估围绕此的真正转化进展，以帮助护理人员和患者进行评估。总体而言，关于 T-PLL 病理生物学的当代概念浓缩在一个全面的机制性疾病模型中，并突出了由此衍生的有前景的干预策略。
