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

TCL1 与 T-PLL 中 T 细胞受体信号传导的致癌协同作用

基本信息

  • 批准号:
    234437523
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    德国
  • 项目类别:
    Research Units
  • 财政年份:
    2013
  • 资助国家:
    德国
  • 起止时间:
    2012-12-31 至 2022-12-31
  • 项目状态:
    已结题

项目摘要

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.
T细胞幼淋巴细胞白血病(T-PLL)是最常见的白血病性成熟T细胞淋巴瘤(MTCL)。它是一种预后差,但研究不足的肿瘤。其标志是T细胞白血病1(TCL 1)癌基因的组成性转录激活。这种在分化的外周T细胞中持续的TCL 1表达被认为是T-PLL的起始事件。然而,还没有确定TCL 1究竟如何发挥致白血病作用。基于最初的观察,我们提出蛋白激酶调节,特别是在T细胞受体(TCR)激活的背景下,是一个中心机制。我们通过利用两个PI建立的有价值的工具来解决这个问题:(a)大量收集具有确定的TCR和TCL 1状态的细胞系系统和充分表征的T-PLL样品;(B)模拟人类T-PLL的TCL 1驱动的白血病的本地小鼠模型,可以进入早期疾病阶段;和(c)嵌合抗原受体(汽车),作为工程化TCR模拟物,其允许询问确定的信号传导组分的重要性。通过资助第一阶段的进展,也涉及与RP 2-4的合作,我们得出了以下需要进一步改进和验证的中心概念:T-PLL是TCR驱动的发病机制的典型MTCL,其中TCL 1作为中心癌基因,充当TCR信号输入的增强子,通过该增强子,存在利用低水平TCR活化朝向转化积累记忆型细胞的倾向。因此,我们将在第二阶段的详细机制的TCR输入和TCL 1的联合行动,在白血病发展的某些阶段,TCL 1/TCR信号的促肿瘤合作的兼性或强制性的相关性,T细胞分化阶段,最容易受到TCL 1 s influence的TCR信号,和分子的脆弱性,可以推断为干预开发。详细地说,我们在目的I中研究了TCR/辅助受体组分或分支优先受到TCL 1的影响。目的II评估紧张性TCR信号传导的促白血病合作的背景下,过度表达的TCL 1解决暴露的T细胞阶段与白血病阶段。我们将以相反的方式消除Aim III中的TCR输入,并通过建立早期和明显白血病阶段TCR信号输入的差异必要性。最后,在目的IV中,我们试图鉴定在TCR信号传导的背景下通过TCL 1的特定指令定义的分子靶标,其可用于抗白血病潜力。拟议的研究将为RP 3的竞争系统提供数据,并开发关于微环境输入触发的RP 4细胞内信号传导的致癌调节的计算机模拟模型。最终,通过推进TCL 1驱动的白血病发生的概念,我们的工作也将有助于更好地理解T细胞稳态紊乱的一般方面。

项目成果

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Professor Dr. Hinrich Abken其他文献

Professor Dr. Hinrich Abken的其他文献

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{{ truncateString('Professor Dr. Hinrich Abken', 18)}}的其他基金

Antigen driven cooperation of two single-chain receptors (immunoreceptors) to recognize defined antigen patterns by engineered T cells
抗原驱动两个单链受体(免疫受体)的合作,以识别工程 T 细胞定义的抗原模式
  • 批准号:
    93427350
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Adoptive Immuntherapie mit rekombinanten Rezeptoren: Evaluierung in einem präklinischen Maus-Modell
重组受体过继免疫疗法:临床前小鼠模型的评估
  • 批准号:
    5399714
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Immunologische Charakterisierung CD7-negativer T-Zellen
CD7 阴性 T 细胞的免疫学特征
  • 批准号:
    5395988
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Herstellung und Charakterisierung von anti-MUC1-scFv-Interleukin-2 Antikörper-Zytokin-Fusionsproteinen für die Immuntherapie zur Aufhebung der MUC1-induzierten, lokalen zellulären Immunsuppression durch MUC1-positive Karzinome
用于免疫治疗的抗 MUC1-scFv-interleukin-2 抗体-细胞因子融合蛋白的生产和表征,以逆转 MUC1 阳性癌症引起的 MUC1 诱导的局部细胞免疫抑制
  • 批准号:
    5211008
  • 财政年份:
    1999
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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