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

为了评估成熟T细胞转化为癌基因的能力，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容易诱导小鼠t细胞白血病/淋巴瘤。然而，成熟T细胞受体（TCR）多克隆T细胞不能转化。令人惊讶的是，TCR准单克隆T淋巴细胞（OT-I）以与干细胞相同的动力学和效率转化。在正在进行的DFG项目（LA1135/9-1）中，我们可以转化进一步的TCR单克隆t细胞类型（P14），表明该观察结果是普遍现象。此外，我们发现添加多克隆t细胞群可以预防恶性肿瘤，我们排除了免疫过程作为控制因素。正如正常t细胞稳态所描述的那样，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，这是拟议研究单位（CONTROL-T）内几个项目的潜在假设。我们的实验观察清楚地表明，tcr多克隆性可以阻止外周t细胞肿瘤的生长。我们计划分析白血病/淋巴瘤发展中的群体动力学，并阐明在tcr -多克隆情况下控制t细胞恶性肿瘤发展的分子机制。此外，我们的实验系统与评估基于逆转录病毒载体的t细胞基因治疗的安全性高度相关。

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.