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

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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.