The current interpretation of chronic lymphocytic leukemia (CLL) as a malignancy characterized by the accumulation of lymphocytes reluctant to undergo apoptosis has to be consistent with the need for a proliferative compartment that keeps nourishing the accumulation compartment. As virtually all circulating CLL lymphocytes are long-lived elements arrested in the G0/early G1 phase of the cell cycle, it may be asked to what extent CLL cells proliferate and how the neglected aspect of proliferation relates to the disease's natural history. These questions are even more relevant as the analysis of immunoglobulin heavy chain variable region (IgVH) sequences has revealed 2 molecularly recognizable distinct clinical entities, mutated and unmutated CLL, the median survival of mutated CLL being significantly longer.1,2 IgVH somatic hypermutations increase diversity of the B-cell receptor (BCR) during T-cell–dependent normal immune responses that occur within germinal centers (GCs). It is thus generally accepted that the mutated CLL cell has transited through the GC and that antigen (Ag) stimulation may influence the disease evolution. The phenotype of unmutated cases resembles that of Ag-experienced B cells,3 suggesting some sort of Ag contact also in unmutated cases.
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