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

B细胞受体（BCR）通路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通路抑制剂的鼓励活性表明病理性BCR信号传导的关键作用。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，但它们在促进B细胞扩增方面的意义已被BCR内部表位介导的自主信号传导的最新数据所质疑。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CLL和潜在MCL中真正的肿瘤促进剂仍有待进一步阐明。在这个研究项目中，我们希望剖析外部触发与自主BCR通路激活在CLL和MCL各自的意义。因此，将在用这些受体稳定转导的BCR阴性细胞系中检测单个CLL和MCL BCR的肿瘤促进能力。用表位模拟肽和抗原进行的转导和刺激实验将揭示BCR是否独立于外部信号支持存活和扩增，如果不是，什么样的共信号是必需的。此外，通过使用基于SH2的全局信号传导测定，我们希望了解不同的BCR类别（CLL与MCL，定型与独特，突变与未突变）是否显示出不同的信号传导模式和促进细胞存活的能力，以及这与临床疾病进程的相关性。此外，我们的目标是鉴定BCR下游的新靶点，这些靶点可能与病理信号网络有关，并可能适用于治疗靶点。我们期望该项目将有助于塑造我们关于BCR作为CLL和MCL的肿瘤促进剂的想法，甚至可能具有鉴定新的、药理学或治疗相关靶点的潜力。

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.