Chronic lymphocytic leykemia ontogenesis: immunogenetic evidence

.Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. It is an incurable disease, yet very heterogeneous in terms of clinical course and outcome, most probably reflecting underlying biological heterogeneity. Over the last decades, it became obvious that CLL is subdivided in categories with distinct biological characteristics, regarding both the genomic and epigenetic profile (however without certain defects being detected in a large proportion of patients) , as well as structural and signaling features of the clonotypic B-cell receptor immunoglobulin (BcR IG)247. Immunogenetic analysis of the clonotypic BcR IG has proved to be instrumental, not only for understanding the pathogenesis of CLL but also for defining clinical subgroups with strikingly different behavior and outcome. That said, the full potential of the IG molecule was not immediately realized, rather initial studies62-64 set in action a train of events culminating with the current notion that CLL is an antigen-driven disease74,76,100. Nowadays, the successful development of drugs targeting the BcR signaling pathway is revolutionizing CLL therapeutics214,216. Besides BcR signaling, CLL clones appear to actively interact with their microenvironment, receiving prosurvival and proliferation signals while at the same time efficiently escaping immune surveillance217,219. Immunomodulatory drugs acting at the level of the immune synapse between clonal B cells and their cognate T cells are currently being tested in clinical trials with promising results218,231. The immunogenetic approach of CLL pathogenesis needs to be able to also explain the existence of CLL-like monoclonal B-cell lymphocytosis (MBL). The term describes the presence of a clonal B cell expansion with CLL immunophenotype in the peripheral blood, at a size that does not reach the consensus cut-off for CLL diagnosis (i.e.