New insights into the phenotype and cell derivation of B cell chronic lymphocytic leukemia

For many decades, B cell chronic lymphocytic leukemia (B-CLL) stood out as a B cell-derived malignancy that was difficult to position within the framework of the available B cell differentiation scheme: First, the histology as well as the immunophenotype did not quite resemble that of any normal lymphocyte; second, in contrast to almost all other B cell tumor subtypes, the immunoglobulin variable region (IgV) genes of B-CLL cases could be either unmutated or somatically mutated; third, the genomic lesions observed in B-CLL were markedly distinct from those of the other major B cell malignancies, which typically exhibit balanced chromosome translocations. Recent advances in the characterization of both B-CLL and normal B cell subpopulations by phenotypic analysis, global gene expression profiling, as well as extensive IgV gene repertoire analyses have shed new light on the phenotype and the cell derivation of B-CLL and provided novel hypotheses concerning its pathogenesis. Here we summarize recent work relevant to these issues and conclude that B-CLL may be derived from a cell that can be referred to as a marginal zone B cell. Moreover, we propose that the lack of chromosomal translocations in B-CLL may be related to their derivation from marginal zone B cells, since somatic hypermutation and Ig class switch, the processes that generate chromosome translocations in most germinal center (GC)-derived malignancies, are no longer active in marginal zone B cells. Also, we discuss similarities and differences between B-CLL and hairy cell leukemia (HCL) and suggest that also HCL may be derived from a post-GC memory or marginal zone B cell therapy. Unfortunately, the genetic alterations that are associated with the pathogenesis of this disease are still obscure.