Correspondence
The Advantage of Rearranging bcl-6
N Engl J Med 1994; 331:1459-1460November 24, 1994
- Article
To the Editor:
In his editorial on the article by Offit and colleagues (July 14 issue),1 Kluin2 concludes that “it is intriguing that activation of the bcl-6 gene seems to be disadvantageous to lymphoma cells: movement of the gene to a new chromosome apparently curtails the malignant behavior of the tumor.” Kluin confronts us with a riddle, because it is difficult to see how any disadvantageous mutation in a malignant cell could lead to a clonal overgrowth of that cell and its progeny.
There is no need to conclude that bcl-6 “curtails the malignant behavior of the tumor.” Genotypically, diffuse large-cell lymphomas constitute a heterogeneous group of tumors; apparently, different kinds of genetic damage lead to the same morphologic and immunologic tumor phenotype. Diffuse large-cell lymphomas also differ biologically, probably because of differences in genetic damage. Bearing this in mind, we could hypothesize that diffuse large-cell lymphomas lacking bcl-6 activation more commonly harbor other genetic lesions that confer aggressive biologic behavior than do lymphomas with activated bcl-6. Reformulated in Kluin's teleologic terminology, this would suggest that bcl-6 activation is no doubt advantageous to the tumor cells, but that other oncogene activations, more common in other examples of diffuse large-cell lymphoma, are even more advantageous. Thus, as compared with tumors lacking activated bcl-6, those with activated bcl-6 appear to be at a relative disadvantage. In this way an erroneous impression is created that activated bcl-6 “apparently curtails the malignant behavior of the tumor.”
2 ReferencesWolter J. Mooi, M.D.
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands1
Offit K ,Lo Coco F ,Louie DC , et al. Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med 1994;331:74-80
Full Text | Web of Science | Medline2
Kluin PM . bcl-6 in lymphoma -- sorting out a wastebasket? N Engl J Med 1994;331:116-118
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Mooi gives an obvious, apparently simple solution for my riddle regarding bcl-6 rearrangements in large-cell lymphoma. In part, the issue he raises is semantic, because the in vivo behavior of a tumor and the prognosis for the patient can only be determined in relation to what is known about other tumors and other patients. My suggestion that rearrangement of bcl-6 in large-cell lymphoma “apparently curtails the malignant behavior of the tumor” does not necessarily relate to the early steps in oncogenesis; it could be that the rearrangement induces a phenotype that inhibits other genetic events or the expression of other oncogenes. Alternatively, expression of the bcl-6 gene may directly or indirectly enhance the sensitivity of the tumor to cytotoxic drugs.
Several arguments suggest that rearrangement of bcl-6 has a positive influence on prognosis. In the series of Offit et al., patients with large-cell lymphomas who harbored a rearrangement of bcl-6 had an excellent prognosis, with a projected survival of 91 percent and a projected rate of freedom from disease of 82 percent at 36 months. This result, remarkable for a very heterogenous disorder with multiple bad prognostic factors, points to a “common” genetic factor.
Mooi suggests that other genetic abnormalities may cause the poor prognosis in patients with large-cell lymphomas lacking a bcl-6 rearrangement. Offit et al. studied this possibility with regard to the two most common oncogenes, bcl-2 and myc. Rearrangements of these genes were not independently related to prognosis. Thus, according to Mooi, there should be as yet unidentified genetic events. Bastard et al.1 found that almost all lymphomas with a rearrangement of band 3q27 had complex cytogenetic abnormalities. Generally, complex karyotypes are associated with an adverse prognosis. Although the series of Bastard and Offit differ, this suggests a beneficial prognostic factor in Offit's group of large-cell lymphomas with rearrangement of bcl-6.
It is not unprecedented to propose that the activation of an oncogene may confer a certain disadvantage to the tumor. In Burkitt's lymphoma, activation of myc by t(8;14) is a prerequisite for tumorigenesis; at the cellular level, myc enhances cell proliferation and blocks differentiation. On the other hand, myc also induces apoptosis of tumor cells, which might be regarded as a disadvantage.2,3
3 ReferencesPhilip M. Kluin, M.D.
University of Leiden, 2300 RC Leiden, the Netherlands1
Bastard C ,Tilly H ,Lenormand B , et al. Translocations involving band 3q27 and Ig gene regions in non-Hodgkin's lymphoma. Blood 1992;79:2527-2531
Web of Science | Medline2
Bissonnette RP ,Echeverri F ,Mahboubi A ,Green DR . Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 1992;359:552-554
CrossRef | Web of Science | Medline3
Fanidi A ,Harrington EA ,Evan GI . Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature 1992;359:554-556
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Mooi's hypothesis is consistent with an analysis of the subgroup of 65 karyotypically abnormal large-cell lymphomas in our series.1 Karyotypic complexity, as measured by the mean number of marker chromosomes (M), calculated as described elsewhere,2 was greater for the group with germ-line bcl-6 (M = 6.1) than for the group with bcl-6 rearrangement (M = 4.4, P = 0.1). This suggests that the bcl-6 germ-line group may have had additional genetic abnormalities, some of which were associated with progression and poor clinical outcome.3
3 ReferencesKenneth Offit, M.D.
R.S.K. Chaganti, Ph.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 100211
Offit K ,Lo Coco F ,Louie DC , et al. Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med 1994;331:74-80
Full Text | Web of Science | Medline2
Offit K ,Jhanwar SC ,Ladanyi M ,Filippa DA ,Chaganti RS . Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: correlations between recurrent aberrations, histology, and exposure to cytotoxic treatment. Genes Chromosomes Cancer 1991;3:189-201
CrossRef | Web of Science | Medline3
Offit K ,Chaganti RS . Chromosomal aberrations in non-Hodgkin's lymphoma: biological and clinical correlations. Hematol Oncol Clin North Am 1991;5:853-869
Web of Science | Medline
