Ighv And Bcl6 Mutational Analysis In

SHM of the IGHV gene segments is an essential component in the generation of high affinity antibodies during the immune response. This process introduces targeted mutations primarily into the complementarity determining regions (CDRs) of productively rearranged IGHV segments at extremely high rates. IGHV mutational analysis should reflect the history of a B cell: mutations indicate encounter with antigen in the germinal center, while unmutated IGHV sequences indicate antigen naïve B cells. SHM is potentially a dangerous, mutagenic process, and errors in SHM have been implicated in the pathogenesis of B-cell lymphomas through the generation of IG chromosomal translocations. SHM may also act on other non-IG genes in both normal and malignant B cells.

Mutational analysis of IGHV gene segments in CLL has been and continues to shed significant light on the pathogenesis of the disease (reviewed in Refs. 16 and 35). In 1999, two groups independently showed that the presence or absence of IGHV mutations defined prognostically important subgroups of CLL; patients lacking IGHV mutations fared worse than patients with mutated sequences. One simple interpretation of these data is that the unmutated CLL represents malignant transformation of antigen naïve B cells. However, these data are not consistent with either the activated B-cell phenotype of CLL, or the gene expression profile, both of which are most similar to memory B cells with continued environmental stimulation.

Mature B cells depend on maintained stimulation via the BCR for antigen, and loss of this complex results in rapid B-cell death by apoptosis.36 One possible explanation for the presence of unmutated IGHV in CLL might be the strength of antigenic stimulation with persistent environmental or autoantigenic stimulation driving at least the early phases of development of the neoplastic clone. Such cells might persist and be antigenically challenged without negotiating a classical germinal center reaction. If persistent exogenous antigenic stimulation were confirmed, it would be analogous to the development of extranodal mucosa-associated lymphoid tissue lymphomas, which have been shown to be dependent on chronic antigenic stimulation of an increasing number of microbial antigens.37 Consistent with this hypothesis of recurrent anti-genic stimulation is the restricted IGHV and IG light chain (IGL) repertoires in at least some cases of CLL.35'38'39 Individual IGHV segments tend either to be mutated or unmutated and to have similar if not identical CDRs. For instance, in one study of class-switched non-IgM producing CLL, five cases of sIgG+ CLL were found to share CDR motifs not only in the heavy chain but also in the light chain. Three-dimensional modeling indicated that these antibodies could bind the same antigenic epitope. On the basis of the restricted antibody responses to carbohydrate antigens, it was suggested that this epitope might be a carbohydrate determinant.38 In a study of 1220 CLL patients, 164 (13.8%) had VH1-69 and of these 163 were in germline configuration39; moreover, there appeared to be marked restriction in the CDR3 region in at least 15 of these patients, who also had the same light chain gene. These data suggest that there is either a strong antigenic selection process, or that B cells bearing this particular combination of IG recombination events are somehow more sensitive to transformation. The presence of such restricted antibody specificities allows new experimental approaches into the pathogenesis of CLL.

However, not all mutated CLL behave "well." It is apparent from several series that patients with mutations in the IGHV3-21 segment have progressive disease.40 In at least some cases this would appear to be due to an association with the TP53 mutation.41

BCL6 mutations, clustering within the region subject to chromosomal translocations in follicular and DLBCL and presumably arising due to the actions of SHM, have been reported in CLL.34 In two reports there was concordance between presence of IGHV mutations, but not in the third. This controversy remains to be resolved. In contrast to DLBCL, where SHM-induced mutations may commonly occur in other proto-oncogenes, such mutations appear to be rare in CLL.

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