Homeostatic niches-control mechanisms in mature T-cell leukemia/lymphoma

为了评估成熟T细胞致癌转化的能力，我们在成熟T细胞或造血干细胞/祖细胞(HSC/HPC)中过表达不同的T细胞(原)癌基因。我们发现转导的HSC/HPC很容易诱发小鼠T细胞白血病/淋巴瘤。然而，成熟的T细胞受体(TCR)多克隆T细胞不能转化。非常令人惊讶的是，TCR准单克隆T淋巴细胞(OT-I)转化的动力学和效率与干细胞相同。在一个正在进行的DFG项目(LA1135/9-1)中，我们可以进一步转化TCR单抗T细胞类型(P14)，这表明这种观察是一个普遍现象。此外，我们发现，多克隆T细胞群的增加可以预防恶性肿瘤，我们排除了免疫过程作为控制因素。正如对正常T细胞稳态的描述，我们假设，白血病前期克隆的生长是由不同T细胞克隆对刺激MHC-自肽生态位的竞争控制的，这是拟议的研究单位(CONTROL-T)内几个项目的基本假设。我们的实验观察清楚地表明，TCR-多克隆可以防止外周T细胞肿瘤的生长。我们计划分析白血病/淋巴瘤发展中的种群动态，并阐明在TCR-多克隆方案中控制T细胞恶性肿瘤发展的分子机制。此外，我们的实验系统对于评估基于逆转录病毒载体的T细胞基因治疗的安全性具有很高的相关性。

To assess the capacity of mature T cells to become oncogenetically transformed we overexpressed different T-cell (proto-)oncogenes in mature T cells or hematopoietic stem cells/progenitor cells (HSC/HPC). We found that transduced HSC/HPC readily induced T-cell leukemia/lymphoma in mice. However, mature T-cell receptor (TCR) polyclonal T cells could not be transformed. Quite surprisingly, TCR quasi-monoclonal T lymphocytes (OT-I) were transformed with the same kinetics and efficiency as stem cells. Within an ongoing DFG project (LA1135/9-1) we could transform a further TCR monoclonal T-cell type (P14), indicating that this observation is a general phenomenon. Moreover, we found that addition of polyclonal T-cell populations prevented malignancies and we excluded immunological processes as a controlling factor. As it is described for normal T-cell homeostasis, we hypothesize, that outgrowth of pre-leukemic clones is controlled by the competition of different T-cell clones for stimulatory MHC-self-peptide niches, an underlying hypothesis of several projects within the proposed research unit (CONTROL-T). Our experimental observations clearly demonstrate that outgrowth of peripheral T-cell tumors is prevented by TCR-polyclonality. We plan to analyze the population-dynamics in leukemia/lymphoma development and to elucidate the molecular mechanisms that control the development of T-cell malignancies in the TCR-polyclonal scenario. Furthermore, our experimental system is highly relevant for evaluating the safety of retroviral vector-based T-cell gene therapy.