In vitro and in vivo modeling of helix-loop-helix protein-mediated reprogramming and malignanttransformation of lymphoid cells

螺旋-环-螺旋蛋白介导的淋巴细胞重编程和恶性转化的体外和体内建模

• 批准号: 242708166
• 负责人: Dr. Martin Janz
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/242708166?language=en
• 关键词: vitro; vivo; modeling; helix; loop

Oncogenic transformation is not only characterized by an enhanced proliferative capacity and/or higher apoptosis resistance of malignant cells, but also by a disruption of the physiological differentiation process. As a consequence, tumor cells can display features of lineage infidelity or even cellular reprogramming that might open up alternative growth and survival pathways. A number of lymphoid malignancies display a phenotype that is in accordance with such a reprogramming process, with classical Hodgkin lymphoma (cHL) being the most prominent example: in striking contrast to their origin from B-cells, the malignant Hodgkin-/Reed-Sternberg (HRS) cells of cHL have almost completely lost their B cell-specific gene expression program and have acquired the expression of genes characteristic for other hematopoietic lineages. In our previous work, we could demonstrate that functional inhibition of the B cell-associated helix-loop-helix transcription factor E2A by its antagonists ID2 and ABF1 represents a key event in this reprogramming process. In further work, we have generated Id2 and Abf1 transgenic mice, which show a profound disturbance of B cell differentiation, a phenotype that we consider as a first step towards an in vivo model of cHL. In addition, we have demonstrated that activation of B lineage-inappropriate signaling pathways, such as the LTR-driven expression of the myeloid CSF1 receptor, are required for growth and survival of HRS cells. In an extension of these findings, we plan to address the following topics in our current proposal: I) We will cross Id2 and Abf1 transgenic mice with mouse strains that carry key cHL-specific oncogenic defects driving growth and survival to promote the generation of a cHL in vivo model. II) We will analyze the capacity and the molecular action of lineage-inappropriate genes to induce reprogramming of B cells and to confer B cell receptor (BCR)-independent survival in the wild-type setting and in the context of reduced E2A activity. III) We will characterize the role of newly identified E2A target genes for malignant transformation of lymphoid cells in vitro and in vivo. Apart from insights into the (de)-differentiation and transformation process of lymphoid cells, our proposal seeks to identify new therapeutic targets for the treatment of human lymphomas, in particular for the growing number of human lymphomas with altered E2A activity.

致癌性转化的特征不仅在于恶性细胞的增殖能力增强和/或更高的凋亡抗性，而且还在于生理分化过程的破坏。因此，肿瘤细胞可以表现出谱系不忠甚至细胞重编程的特征，这可能会开辟替代的生长和生存途径。许多淋巴恶性肿瘤显示出与这种重编程过程一致的表型，经典霍奇金淋巴瘤（cHL）是最突出的例子：与它们来自B细胞形成鲜明对比，cHL的恶性Hodgkin-/Reed-Sternberg（HRS）细胞几乎完全丧失了它们的B细胞，特异性基因表达程序，并获得了其他造血谱系的基因特征表达。在我们以前的工作中，我们可以证明，B细胞相关的螺旋-环-螺旋转录因子E2 A的拮抗剂ID 2和ABF 1的功能抑制代表了这个重编程过程中的一个关键事件。在进一步的工作中，我们已经产生了Id 2和Abf 1转基因小鼠，这显示出B细胞分化的严重障碍，我们认为这是迈向cHL体内模型的第一步。此外，我们已经证明，激活B谱系不适当的信号传导途径，如LTR驱动的髓样CSF 1受体的表达，是HRS细胞生长和存活所必需的。在这些发现的扩展中，我们计划在我们当前的提案中解决以下主题：I）我们将使Id 2和Abf 1转基因小鼠与携带驱动生长和存活的关键cHL特异性致癌缺陷的小鼠品系杂交，以促进cHL体内模型的产生。II）我们将分析谱系不适当基因诱导B细胞重编程和在野生型环境和E2 A活性降低的背景下赋予B细胞受体（BCR）非依赖性存活的能力和分子作用。III）我们将描述新鉴定的E2 A靶基因在体外和体内淋巴细胞恶性转化中的作用。除了对淋巴细胞的（去）分化和转化过程的了解外，我们的建议还旨在确定用于治疗人类淋巴瘤的新治疗靶点，特别是用于越来越多的具有改变的E2 A活性的人类淋巴瘤。