The oncogenic cooperation of TCL1 with T-cell receptor signaling in T-PLL

T细胞前淋巴细胞白血病(T-PLL)是最常见的白血病成熟T细胞淋巴瘤(MTCL)。这是一种预后不佳，但研究不足的肿瘤。其特点是T细胞白血病1(TCL1)癌基因的结构性转录激活。这种持续的TCL1在分化中的外周T细胞中的表达被认为是T-PLL的启动事件。然而，目前还不能确定TCL1究竟是如何导致白血病的。根据最初的观察，我们提出蛋白激酶的调节，特别是在T细胞受体(TCR)激活的背景下，是一个中心机制。我们利用了两个PI建立的有价值的工具来解决这个问题：(A)定义了TCR和TCL1状态的细胞系系统的大量集合，以及特征良好的T-PLL样本；(B)模仿人类T-PLL的TCL1驱动的原生小鼠模型，可以进入疾病的早期阶段；以及(C)嵌合抗原受体(CARS)，作为工程TCR模拟，允许询问定义的信号成分的重要性。通过资金阶段I的进展，也包括与RPS 2-4的合作，我们得出了以下需要进一步完善和验证的核心概念：T-PLL是TCR驱动的发病机制的典范MTCL，TCL1作为中央癌基因作为TCR信号输入的增强器，通过TCR信号输入有积累记忆类型细胞的倾向，利用低水平的TCR激活进行转化。因此，我们将在第二阶段解决TCR输入和TCL1联合作用的详细机制，TCL1/TCR信号在白血病发展的某些阶段的促肿瘤合作的兼性或强制性相关性，最容易受到TCL1影响的T细胞分化阶段，以及可以推断的介入开发的分子脆弱性。在Aim I中，我们详细研究了TCL1优先影响TCR/辅受体的哪些成分或分支。目的II评估在暴露的T细胞阶段与白血病阶段过表达的TCL1被解决的背景下，紧张性TCR信号对白血病的促进作用。相反，我们将消融AIM III中的TCR输入，并由此确定早期和显性白血病阶段TCR信号输入的区别必要性。最后，在目标IV中，我们试图确定在TCR信号背景下通过TCL1的特定指令定义的分子靶点，这些靶点在药理上可用于抗白血病潜力。所提出的研究将为RP3的竞争系统和正在开发的环境输入触发的Rp4细胞内信号的致癌调控的电子模型提供数据。最终，通过提出TCL1驱动的白血病发生的概念，我们的工作也将有助于更好地了解扰乱的T细胞稳态的一般方面。

T-cell prolymphocytic leukemia (T-PLL) is the most common leukemic mature T-cell lymphoma (MTCL). It is a poor prognostic, yet understudied tumor. Its hallmark is the constitutive transcriptional activation of the T-cell leukemia 1 (TCL1) oncogene. This persistent TCL1 expression in the differentiating peripheral T-cells is considered the initiating event towards T-PLL. However, it is not established how exactly TCL1 acts leukemogenic. Based on initial observations, we proposed that protein-kinase modulation, especially in the context of T-cell receptor (TCR) activation, is a central mechanism. We addressed this by capitalizing on valuable tools established by both PIs: (a) large collections of cell-line systems of defined TCR and TCL1 status and of well-characterized T-PLL samples; (b) autochthonous mouse models of TCL1-driven leukemia mimicking human T-PLL with access to early disease stages; and (c) chimeric antigen receptors (CARs) as engineered TCR mimics allowing interrogations of the importance of defined signaling components. Through the progress in funding phase-I, also involving collaborations with RPs 2-4, we arrived at the following central concept that requires further refinements and validations: T-PLL is a paradigmatic MTCL for a TCR-driven pathogenesis with TCL1 as the central oncogene acting as an enhancer of TCR-signal input through which there is a propensity of accumulating memory-type cells utilizing low-level TCR activation towards transformation. Consequently, we will address in phase-II the detailed mechanisms of the combined action of TCR input and TCL1, the facultative or obligatory relevance of a pro-tumorigenic cooperation of TCL1/TCR signaling at certain phases of leukemic development, the T-cell differentiation stage that is most susceptible to TCL1s in-fluence on TCR signaling, and molecular vulnerabilities that can be deduced for interventional exploitations. In detail, we study in Aim I which TCR/coreceptor components or branches are preferentially impacted by TCL1. Aim II assesses the pro-leukemic cooperation of tonic TCR signaling in the context of overexpressed TCL1 resolved for the exposed T-cell stage vs leukemic phase. In an opposite fashion we will ablate TCR input in Aim III and by that establish the differential necessity of TCR signaling input at early and overt leukemic stages. Finally, in Aim IV we seek to identify molecular targets defined through a specific instruction by TCL1 in the context of TCR signaling that are pharmacologically exploitable for an anti-leukemic potential. The proposed studies will data-feed the competition systems of RP3 and the developing in-silico models on oncogenic modulation of milieu-input triggered intracellular signaling of RP4. Ultimately, by advancing the concepts of TCL1-driven leukemogenesis, our work will also serve to better understand general aspects of perturbed T-cell homeostasis.