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）途径激活可能会驱动某些形式的B细胞淋巴瘤的发展和进展。慢性淋巴细胞性白血病（CLL）和地幔细胞淋巴瘤（MCL）是支持这一概念的范式疾病，因为BCR的结构限制并鼓励BCR途径抑制剂的活性表明病理BCR信号的至关重要。虽然普遍存在的自身抗原无疑与CLL中表达的许多BCR相互作用，但通过近最新的关于由BCR内部表位介导的自主信号传导的数据，它们在促进B细胞膨胀方面的重要性受到了质疑。如果以及如何将外部和自主受体激活融合在一起，并将B细胞受体组合在一起，将B细胞受体进入CLL和潜在的MCL中的肿瘤启动子仍然尚待进一步阐明。在该研究项目中，我们希望剖析CLL和MCL中外部触发与自主BCR途径激活的各自的意义。因此，将在用这些受体稳定转导的BCR阴性细胞系中测试单个CLL和MCL BCR的肿瘤促进能力。模仿肽和抗原的表位的转导和刺激实验将揭示BCR是否支持生存和扩展，而不是独立于外部信号，并且 - 如果不是 - 哪种共同信号是必不可少的。此外，通过使用基于SH2的全局信号传导测定法，我们希望找出不同的BCR类别（CLL与MCL，刻板印象与独特，突变与未成型）是否显示出不同的信号传导模式和能力，以促进细胞存活以及这与临床疾病课程的相关性。此外，我们旨在确定BCR下游的新颖目标，这可能与病理信号网络有关，并可能与治疗性靶向有关。我们期望该项目将有助于将我们作为CLL和MCL中的BCR作为肿瘤启动子的想法，甚至可能有潜在地识别小说，预测，并且在预测上有相关的目标。