Braun Till, Stachelscheid Johanna, Bley Nadine, Oberbeck Sebastian, Otte Moritz, Müller Tony Andreas, Wahnschaffe Linus, Glaß Markus, Ommer Katharina, Franitza Marek, Gathof Birgit, Altmüller Janine, Hallek Michael, Auguin Daniel, Hüttelmaier Stefan, Schrader Alexandra, Herling Marco
Department I of Internal Medicine, Center for Integrated Oncology, Aachen-Bonn-Cologne-Duesseldorf, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Charles Tanford Protein Center, Halle, Germany.
Cancer Res. 2022 May 3;82(9):1818-1831. doi: 10.1158/0008-5472.CAN-21-1908.
T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-refractory T-cell malignancy with limited therapeutic options and a poor prognosis. Current disease concepts implicate TCL1A oncogene-mediated enhanced T-cell receptor (TCR) signaling and aberrant DNA repair as central perturbed pathways. We discovered that recurrent gains on chromosome 8q more frequently involve the argonaute RISC catalytic component 2 (AGO2) gene than the adjacent MYC locus as the affected minimally amplified genomic region. AGO2 has been understood as a protumorigenic key regulator of miRNA (miR) processing. Here, in primary tumor material and cell line models, AGO2 overrepresentation associated (i) with higher disease burden, (ii) with enhanced in vitro viability and growth of leukemic T cells, and (iii) with miR-omes and transcriptomes that highlight altered survival signaling, abrogated cell-cycle control, and defective DNA damage responses. However, AGO2 elicited also immediate, rather non-RNA-mediated, effects in leukemic T cells. Systems of genetically modulated AGO2 revealed that it enhances TCR signaling, particularly at the level of ZAP70, PLCγ1, and LAT kinase phosphoactivation. In global mass spectrometric analyses, AGO2 interacted with a unique set of partners in a TCR-stimulated context, including the TCR kinases LCK and ZAP70, forming membranous protein complexes. Models of their three-dimensional structure also suggested that AGO2 undergoes posttranscriptional modifications by ZAP70. This novel TCR-associated noncanonical function of AGO2 represents, in addition to TCL1A-mediated TCR signal augmentation, another enhancer mechanism of this important deregulated growth pathway in T-PLL. These findings further emphasize TCR signaling intermediates as candidates for therapeutic targeting.
The identification of AGO2-mediated activation of oncogenic T cells through signal amplifying protein-protein interactions advances the understanding of leukemogenic AGO2 functions and underlines the role of aberrant TCR signaling in T-PLL.
T 细胞原淋巴细胞白血病（T-PLL）是一种化疗难治性 T 细胞恶性肿瘤，治疗选择有限且预后不良。目前的疾病概念认为 TCL1A 癌基因介导的 T 细胞受体（TCR）信号增强和异常 DNA 修复是主要的紊乱途径。我们发现，8q 染色体上的反复增益更频繁地涉及 Argonaute RISC 催化成分 2（AGO2）基因，而不是相邻的 MYC 基因座，作为受影响的最小扩增基因组区域。AGO2 被认为是 miRNA（miR）加工的促肿瘤关键调节因子。在此，在原发性肿瘤材料和细胞系模型中，AGO2 的过度表达与以下情况相关：（i）更高的疾病负担；（ii）白血病 T 细胞体外活力和生长增强；（iii）miR 组和转录组突出显示生存信号改变、细胞周期控制废除和 DNA 损伤反应缺陷。然而，AGO2 在白血病 T 细胞中也引发了直接的、而非 RNA 介导的效应。基因调控 AGO2 的系统显示，它增强 TCR 信号，特别是在 ZAP70、PLCγ1 和 LAT 激酶磷酸化激活水平。在全局质谱分析中，AGO2 在 TCR 刺激的背景下与一组独特的伙伴相互作用，包括 TCR 激酶 LCK 和 ZAP70，形成膜蛋白复合物。它们三维结构的模型还表明，AGO2 会经历 ZAP70 的转录后修饰。AGO2 这种与 TCR 相关的新的非经典功能，除了 TCL1A 介导的 TCR 信号增强外，代表了 T-PLL 中这种重要的失调生长途径的另一种增强机制。这些发现进一步强调 TCR 信号中间体作为治疗靶点的候选者。
通过信号放大蛋白-蛋白相互作用鉴定 AGO2 介导的致癌 T 细胞激活，推进了对白血病源性 AGO2 功能的理解，并强调了异常 TCR 信号在 T-PLL 中的作用。
