Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease.
The BCL-6 gene encoding a nuclear-located Kruppel-type zinc finger protein is rearranged in about 30% diffuse large B-cell lymphomas and is expressed predominantly in normal germinal center B cells and related lymphomas. These findings suggest that BCL-6 may play a role in regulating differentiation of normal germinal center B cells and that its deregulated expression caused by rearrangements may contribute to lymphomagenesis. This prompted us to investigate the expression of the BCL-6 protein in Hodgkin's disease (HD), focusing on the nodular lymphocyte predominance subtype (NLPHD), which differs from classical HD by virtue of the B-cell nature of the malignant cell population (so-called L&H cells) and its relationship with germinal centers. Forty-one HD samples (19 NLPHD, 12 nodular sclerosis, and 10 mixed cellularity) were immunostained with the monoclonal antibodies PG-B6 and PG-B6p that react with a fixative-sensitive and a formalin-resistant epitope on the aminoterminal region of the BCL-6 gene product, respectively. Strong nuclear positivity for the BCL-6 protein was detected in tumor (L&H) cells in all cases of NLPHD. In contrast, BCL-6 was expressed only in a small percentage of Hodgkin and Reed-Sternberg cells in about 30% of classical HD cases. Notably, the nuclei of reactive CD3+/CD4+ T cells nearby to and rosetting around L&H cells in NLPHD were also strongly BCL-6+, but lacked CD40 ligand (CD40L) expression. This staining pattern clearly differed from that of classical HD, whose cellular background was made up of CD3+/CD4+ T cells showing the BCL-6-/CD40L+ phenotype. These results further support the concept that NLPHD is an histogenetically distinct, B-cell-derived subtype of HD and suggest a role for BCL-6 in its development.
Falini
B
B
Institute of Hematology, University of Perugia, Italy.
Bigerna
B
B
Pasqualucci
L
L
Fizzotti
M
M
Martelli
M F
MF
Pileri
S
S
Pinto
A
A
Carbone
A
A
Venturi
S
S
Pacini
R
R
Cattoretti
G
G
Pescarmona
E
E
Lo Coco
F
F
Pelicci
P G
PG
Anagnastopoulos
I
I
Dalla-Favera
R
R
Flenghi
L
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000032:analysis; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D023201:CD40 Ligand; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D054278:Embryonal Carcinoma Stem Cells; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6; D016539:Reed-Sternberg Cells / Q000378:metabolism / Q000473:pathology; D012397:Rosette Formation; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D017252:CD3 Complex; D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D023201:CD40 Ligand