In-depth characterization of the genetic abnormalities and signaling pathways involved in clonal and neoplastic transformation of B cells in subjects with MBL (monoclonal B-cell lymphocytosis) and CLL (chronic lymphocytic leukemia)

Chronic lymphocytic leukaemia (CLL) is the most frequent haematological malignancy in the western world. Currently it is accepted that CLL could be preceded by a clinically silent monoclonal B-cell lymphocytosis (MBL), small mature B-cell clones with a CLL-like phenotype being detected in up to 12% of otherwise healthy adults. This project aims at gaining insight into the genetic characteristics and the intracellular signalling pathways involved in the ontogenesis of MBL and progression of MBL clonal B-cells to CLL. Three study groups will be included: adult healthy donors (non-MBL) representative of the population of Salamanca (n=300), MBL without (n=90) and with lymphocytosis (n=60) and CLL (n=100). In each sample of purified clonal B-cells we will search for the presence of genetic abnormalities, sequence the IGHV/IGKV/IGLV genes and perform a massive SNP genotyping, aimed at identifying differential patterns of genetic alteration/predisposition among the three groups of individuals. In a subgroup of 60 MBL and 30 CLL the genetic study will be completed with the analysis of the length of telomeres and a phenotypic/proteomic characterization of the signalling pathways associated with BCR/CD79, cell proliferation, and senescence. In a subset of 25 biclonal cases (MBL and CLL) we will screen for antigens which bind to the BCR (NAPPA technique), aiming at identifying antigen specificities shared by different clones/cases. Finally, we will determine the relationship existing between the different altered patterns detected (at both the genetic and phenotypic/proteomic levels) and the status of the B-cell expansion, the behaviour of the B-cell clone and patient outcome.