Chronic Lymphocytic Leukemia: Who, How, and Where?

Abstract

Chronic lymphocytic leukemia (CLL) is an extremely fascinating and enigmatic disease where a distinctive homogenous immunophenotype comes along with a remarkable biological and clinical heterogeneity. Key mechanisms underlying CLL onset and progression have been recently dissected. Recent progresses led to the identification of a preneoplastic condition of the disease (i.e., monoclonal B-cell lymphocytosis, MBL) that shed light on very early events responsible for CLL development but also on factors defining the thin red line between clinically overt disease and preclinical condition. The introduction of high-throughput sequencing techniques has increased our knowledge on the complexity of the genomic landscape of CLL cells and introduced the concept of clonal architecture and evolution, proving that both are influenced by any therapeutic intervention and this should be taken into account when selecting time and type of treatment in CLL patients. We gained further knowledge on the role of B-cell receptor (BcR) signaling and accumulated several hints supporting its key role in CLL development and progression. This led, for the first time in CLL history, to a targeted treatment approach, with novel inhibitors now available in the clinical practice for our CLL patients. That notwithstanding, there are many open questions in CLL pathogenesis that need to be addressed, with the next years hopefully leading us to shed light on the complex intertwining between relevant gene mutations and microenvironmental interactions to finally elucidate the pathogenetic mechanisms responsible of the onset of the disease.