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The B-cell receptor as tumor promotor in chronic lymphocytic leukemia and mantle cell lymphoma

B 细胞受体作为慢性淋巴细胞白血病和套细胞淋巴瘤的肿瘤促进剂

基本信息

批准号：
321118409
负责人：
Professorin Dr. Mascha Binder, Ph.D.
金额：
--
依托单位：
Departement Biomedizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/321118409?language=en
关键词：
cell receptor tumor promotor chronic

项目摘要

B-cell receptor (BCR) pathway activation may drive the development and progression of some forms of B-cell lymphomas. Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are paradigm diseases supporting this concept, since structural restrictions of the BCR and encouraging activity of BCR pathway inhibitors suggest a crucial role for pathological BCR signaling. While ubiquitous autoantigens undoubtedly interact with many of the BCRs expressed in CLL, their significance in promoting B-cell expansion has been called into question by more recent data on autonomous signaling mediated by BCR-internal epitopes. If and how external and autonomous receptor activation fit together and render the B-cell receptor into a veritable tumor promotor in CLL and potentially MCL still remains to be further elucidated. In this research project, we wish to dissect the respective significance of externally triggered versus autonomous BCR pathway activation in CLL and MCL. The tumor promoting capacity of individual CLL and MCL BCRs will therefore be tested in BCR-negative cell lines stably transduced with these receptors. Transduction and stimulation experiments with epitope mimicking peptides and antigens will reveal if the BCR supports survival and expansion independently of external signals and - if not - what kind of co-signals are essential. Moreover, by using a global SH2-based signaling assay, we wish to find out if different BCR categories (CLL versus MCL, stereotypic versus unique, mutated versus unmutated) show different signaling patterns and capacities to promote cell survival and how this correlates with clinical disease courses. In addition, we aim at identifying novel targets downstream the BCR, that may be implicated in the pathological signaling network and potentially amenable to therapeutic targeting.We expect that this project will contribute to shaping our ideas about the BCR as tumor promotor in CLL and MCL and may even have the potential to identifiy novel, prognostically or therapeutically relevant targets.

b细胞受体（BCR）通路的激活可能驱动某些形式的b细胞淋巴瘤的发生和进展。慢性淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）是支持这一概念的典型疾病，因为BCR的结构限制和BCR通路抑制剂的活性增强表明病理性BCR信号传导的关键作用。虽然无所不在的自身抗原无疑与CLL中表达的许多bcr相互作用，但最近关于bcr内部表位介导的自主信号传导的数据对其促进b细胞扩增的意义提出了质疑。在CLL和潜在的MCL中，外部和自主受体激活是否以及如何结合在一起并使b细胞受体成为真正的肿瘤启动子仍有待进一步阐明。在本研究项目中，我们希望分析CLL和MCL中外部触发与自主BCR通路激活的各自意义。因此，单个CLL和MCL bcr的促瘤能力将在bcr阴性细胞系中进行测试，这些细胞系稳定地由这些受体转导。表位模拟肽和抗原的转导和刺激实验将揭示BCR是否支持独立于外部信号的生存和扩展，如果不是，什么样的共同信号是必需的。此外，通过使用全球基于sh2的信号分析，我们希望发现不同的BCR类别（CLL与MCL，定型与独特，突变与未突变）是否表现出不同的信号模式和促进细胞存活的能力，以及这与临床疾病病程的关系。此外，我们的目标是确定BCR下游的新靶点，这些靶点可能与病理信号网络有关，并且可能适合治疗靶向。我们期望这个项目将有助于形成我们关于BCR作为CLL和MCL肿瘤启动子的想法，甚至可能有潜力确定新的、预后或治疗相关的靶标。