Structural basis of B-cell Receptor-mediated cell-autonomous signalling in chronic lymphocytic leukaemia
Worldwide Cancer Research
Fondazione Centro San Raffaele
B cell receptor (BcR) signaling is a central event in the pathogenesis of chronic lymphocytic leukemia (CLL). Inhibitors of downstream effectors of BcR signaling display good clinical efficacy, yet have a limited capacity to induce profound clinical responses, and frequently lead to side effects due in part to off-target activity. Thus, the key challenge towards optimal CLL patient management remains the development of tailored treatments that target the BcR-mediated signaling, while taking into account the patient-specific modalities of receptor activation. CLL patients are heterogeneous in leukemic cell phenotype and clinical outcome, but can be grouped in subsets that present homogeneous clinicobiological features based on the expression of highly homologous BcRs. A unique feature of CLL B cells is their ability to signal autonomously in vitro, through homotypic recognition of the BcR. We recently showed that these BcR interactions are different and specific for each subgroup of patients as defined by the receptor structure.  Here, we propose an integrated approach to characterize the structure and self-recognition of BcRs derived from the most common CLL subsets. First, we will determine the high-resolution crystal structures of BcRs from three common stereotyped subsets, as well as non-stereotyped IGHV1-69 receptors. Then, will use mutagenesis and biophysical methods to fully characterize and validate the homotypic binding of the receptors observed in the crystals, and to investigate existing correlations between BcR contacts and clinical course of disease. Finally, we will perform an in silico screening of chemical libraries to identify compounds antagonizing the autologous BcR interaction in the most common CLL cases, and test these in a reconstituted B cell system. The results of the research outlined will widen our knowledge on the mechanism leading to CLL onset, improve patients management, and provide lead compounds against a prevalent form of the disease.
2.1 Biological and endogenous factors