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Letters to the Editor |
Division of Oncology [I. S. L., R. L.] and Department of Pathology [Y. J., M. L. C.], Stanford University Medical Center, Stanford, California 94305
Letter
We read with interest the manuscript of Akasaka et al. (1)
on the molecular anatomy of BCL-6 translocations. The authors analyzed 58 cases carrying a BCL-6 rearrangement and defined a break-point hyper-cluster region located downstream of exon 1. In 19 cases, the break point was located between nucleotides 703–879 of the BCL-6 hypermutational region, according to Migliazza et al. (2)
. Akasaka et al. (1)
also indicate that this break-point hyper-cluster region is located in the major mutation cluster, but they do not elaborate on this issue. Our previous evaluation of the distribution of BCL-6 somatic mutations from a compilation of published lymphoma cases (3)
disclosed that 
35% occurred in the break-point cluster defined by Akasaka et al. (1)
. Moreover, some of the somatic mutations were reported at nucleotide positions where break points were observed (3)
and also in positions corresponding to the probe 6162 (3)
used by Akasaka et al. (1)
in gel mobility-shift assays (Fig. 1)
. The overlap between the hypermutational and the break-point hyper-cluster regions raises the possibility that the same mechanism may be responsible for both processes. Alternatively, the hypermutation process may predispose to chromosomal breaks and subsequent translocations. It has been proposed that the mechanism responsible for somatic mutations in immunoglobulin genes is identical to that in the BCL-6 gene in view of similar features of mutations in both genes (4
, 5)
.
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FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The abbreviation used is: GC, germinal center. 
Received 6/20/00. Accepted 8/ 2/01.
REFERENCES
First Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan
We and others have shown that the BCL6 gene in B-cell neoplasms is affected by two somatic events, i.e., point mutation and chromosomal translocation (1 2 3) . The majority of BCL6 breakpoints and somatic mutations are clustered immediately 3' to exon 1, raising the possibility that the same mechanism is responsible for these two processes. The data presented in the letter by Lossos et al. further confirmed this hypothesis. Because somatic mutations can be observed in memory B cells that are isolated from normal individuals as well as in GC1 B cells from a reactive tonsil (4) , the hypermutation process may be prerequisite to the development of the translocation that leads to neoplastic transformation.
There are many similarities between BCL6 and immunoglobulin heavy-chain variable region genes (IGVH) somatic mutations: (a) both occur in GC B-cells; (b) both occur within or near a RGYW motif; (c) both cluster in regions downstream of promoters of the gene; (d) single nucleotide substitutions are more common than deletions and insertions in both genes; (e) both genes contain a cis-acting transcriptional control element; and (f) BCL6 mutation in chronic lymphocytic leukemia is restricted to cases that carry mutated IGVH (5 6 7) . Thus, it is possible that the immunoglobulin-somatic mutation machinery also targets BCL6, thereby predisposing to chromosomal breaks and subsequent translocations. On the other hand, BCL6 translocation can involve not only immunoglobulin but also a number of non-immunoglobulin loci as partners (1) . Because the number of cases with each non-immunoglobulin/BCL6 translocation is limited, no data are currently available for whether the non-immunoglobulin partners are also targeted by somatic mutations. Recently, GC- and memory B cells were shown to carry mutations within the 5' region of the CD95 gene, which is, in the B-cell lineage, specifically expressed at the GC stage of differentiation (8) . Thus, there is a possibility that a fraction of genes, which are expressed at the GC stage, is targeted by somatic mutation and non-immunoglobulin/BCL6 translocation is a by-product of this process.
As suggested in the letter by Lossos et al., the hypermutation/breakpoint cluster region is close to the regulatory region of BCL6, where sequence-specific DNA-binding sites are identified. Kikuchi et al. (9) found a negative regulatory region that had a potential binding site of Bcl-6. They showed that Bcl-6 can autoregulate its own expression by binding to this region. Thus, somatic mutation as well as small deletion within this particular area is likely to affect expression of the BCL6. However, there is no clear evidence that neoplastic B cells that carry altered BCL6 alleles express increased levels of Bcl-6 protein as compared with those with wild-type BCL6. Moreover, the distribution of BCL6 mutations in neoplastic B cell is not significantly different from that of normal B cells. Thus, additional studies will be required to confirm the pathogenetic role of BCL6 mutation in the development B-cell neoplasms.
Received 6/22/01. Accepted 8/ 2/01.
REFERENCES
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