What is the current evidence for antigen involvement in the development of chronic lymphocytic leukemia?

• For many years it has been evident that B-cell chronic lymphocytic leukemia (CLL) displays preferential usage of individual immunoglobulin (Ig) variable heavy chain (VJapanese sourceH) genes. The VH1-69 gene was the first to be reported overrepresented in a large number of CLL patients, where the VH1-69+ CLL rearrangements showed characteristic molecular features, such as unmutated VH genes, usage of specific diversity/joining gene segments, and a longer than average complementarity determining region (CDR) 3 with certain common amino acid motifs. Also, biased usage of the VH3-07 and VH4-34 genes with specific rearrangement characteristics was reported in CLL. These findings led to the speculation that antigens could be involved during CLL development by triggering proliferation of B-cells with specific B-cell receptors (BCRs) leading to an increased risk of transforming events. Recently, we characterized a subset of CLL utilizing the VH3-21 gene that also displayed peculiar Ig features, e.g. very short and homologous CDR3s, predominant λ expression and preferential Vλ2-14 gene usage. This VH3- 21+ subgroup also had poor prognosis despite the fact that two-thirds of cases carried mutated VH genes. Moreover, we and others have thereafter described further CLL subsets with very similar heavy and light chain gene rearrangement features. These latter findings of subsets expressing restricted BCRs have emphasized the hypothesis that antigens could play a role during the pathogenesis of CLL. Interestingly, recombinant antibodies produced from these restricted subsets showed similar cytoplasmatic reactivity within each group, thus suggesting recognition of a limited number of autoantigens. Further characterization of antigens is now necessary in order to understand their nature and exact role in CLL development.

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