Chronic lymphocytic leukemia (CLL) is a clonal lymphoproliferative disorder that is characterized by the proliferation and accumulation of small, mature CD5+ CD23+ B lymphocytes in the blood, lymph nodes, and bone marrow. CLL is the most common leukemia in Western countries, and the median age at diagnosis is 72years. The clinical course of CLL is highly variable; some patients will present with indolent disease, while others with progressive disease will require specific treatment. CLL is a heterogeneous disease that can be classified into two major subsets depending upon the mutational status of immunoglobulin heavy chain variable region (IGHV) genes encoding part of the B cell receptor (BCR) in CLL cells. In approximately half of cases, leukemic cells harbor somatic mutations in IGHV genes (M-CLL), while the other half are cases of unmutated CLL (U-CLL). The clinical course of these two subsets differ substantially, with U-CLL correlating with other adverse prognostic factors, such as CD38 expression, ζ-chain associated protein kinase 70 (ZAP-70) expression, and cytogenetic alterations, leading to poorer outcomes[2,3].
The origin of CLL is still debated but is critical to the understanding of its pathogenesis. Antigenic stimulation is thought to be crucial for this pathogenesis. Some researchers hold the opinion that the two subsets of CLL derive from distinct cell types with different differentiation and antigen encounter histories. M-CLL cells are hypothesized to arise from post-germinal center B cells, while U-CLL cells may derive from naïve B cells of the natural repertoire aimed against common pathogens and/or autoantigens[4,5]. Another theory has been proposed in which both U-CLL and M-CLL cells derive from marginal zone memory B cells. A recent study also suggested a role for cell-autonomous antigen-independent signaling in CLL pathogenesis, although this theory is controversial as the experiments were conducted ex vivo.