Analysis of BCL-6 mutations in classic Hodgkin disease of the B- and T-cell type.
BCL-6 is essential for germinal center formation and thus for affinity maturation of immunoglobulin (Ig) genes by somatic mutations. The 5'-noncoding region of the BCL-6 gene is even a target for the mutation machinery. Translocations of the BCL-6 gene to heterologous promoters and mutations of its 5'-noncoding regulatory region were reported to be potential mechanisms for deregulating BCL-6 expression and for playing a role in the genesis of non-Hodgkin lymphoma. In line with this hypothesis is the observation that B-cell lymphoma with somatic mutations, such as diffuse large B-cell lymphoma and follicular lymphoma, also carry BCL-6 mutations, some of which are recurrently detectable. Classic Hodgkin disease (cHD) is also derived from B cells with high loads of somatic mutations and thus a further candidate for BCL-6 mutations. To determine the presence and potential role of BCL-6 mutations in cHD, the 5'-noncoding BCL-6 proportion of single Hodgkin and Reed-Sternberg (HRS) cells from 6 cases of cHD and 6 cases of HD-derived cell lines was analyzed. All B-cell-derived HD cases and cell lines harbored BCL-6 mutations. In contrast, both T-cell-derived HD cases and cell lines were devoid of BCL-6 mutations. With only one exception, there were no lymphoma-specific recurrent BCL-6 mutations detected, and BCL-6 protein was absent from the HRS cells of most cases. In conclusion, (1) somatic BCL-6 mutations are restricted to cHD cases of B-cell origin, and (2) the BCL-6 mutations represent mostly irrelevant somatic base substitutions without consequences for BCL-6 protein expression and the pathogenesis of cHD.
Seitz
V
V
Institute of Pathology, Consultation and Reference Center for Lymph Node Pathology and Haematopathology, University Hospital Benjamin Franklin, Free University Berlin, Germany.
Hummel
M
M
Anagnostopoulos
I
I
Stein
H
H
D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000473:pathology*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D005260:Female; D005803:Genes, Immunoglobulin; D005838:Genotype; D006689:Hodgkin Disease / Q000145:classification / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D016539:Reed-Sternberg Cells / Q000737:chemistry; D013601:T-Lymphocytes / Q000473:pathology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*; D014407:Tumor Cells, Cultured
D020121:5' Untranslated Regions; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors