scholarly journals Reed-Sternberg Cells of Classical Hodgkin's Disease React With the Plasma Cell-Specific Monoclonal Antibody B-B4 and Express Human Syndecan-1

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3787-3794 ◽  
Author(s):  
Antonino Carbone ◽  
Annunziata Gloghini ◽  
Valter Gattei ◽  
Massimo Degan ◽  
Salvatore Improta ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Tumor Cells ◽  
Western Blotting ◽  
Plasma Cell ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Cell Phenotype ◽  
Rt Pcr ◽  
Subtype B

Although the cellular origin of Reed-Sternberg (RS) cells of classical Hodgkin's disease (HD) has been a controversial issue for many years, recent immunophenotypic and molecular studies have suggested that RS cells of a subset of classical HD cases may be related to B cells. To further define the immunophenotypic features and the differentiation stage of RS cells, a series of 56 HD samples, including both nodular lymphocyte predominance (LP) (eight cases) and classical HD (nodular sclerosis [NS], 32 cases; mixed cellularity [MC], 16 cases) with a non-T–cell phenotype, were evaluated for the immunohistochemical expression of the B-B4 antigen, a specific marker for terminally differentiated B cells. Because the cDNA of the B-B4 antigen encodes syndecan-1, a member of a family of transmembrane heparan sulfate proteoglycans thought to be involved in binding cells of the B lineage to the interstitial matrix, the B-B4 immunoreactivity was correlated with the expression of syndecan-1 in HD-derived cell lines (L428, KM-H2), as detected by both reverse transcriptase polymerase chain reaction (RT-PCR) studies and Western blotting. Our results show that B-B4 reacts with RS cells and their morphological variants of all cases of classical HD, irrespective of their antigenic phenotype (B, undetermined), albeit at a varying degree of cellular expression. Notably, a high reactivity and staining intensity for the B-B4 monoclonal antibody (MoAb) was restricted to tumor cells from NS HD. In cases of the latter subtype, B-B4 positivity was also found in sclerosis-trapped spindle cells (fibrocytes/fibroblasts). Conversely, the putative tumor cells of nodular LP HD were consistently unreactive with the B-B4 MoAb. Finally, we have demonstrated by RT-PCR, flow cytometry, and Western blotting that cultured RS cells, of B and undetermined phenotype, express syndecan-1 mRNA and produce a form of syndecan-1, recognized by the B-B4 MoAb, which is predominantly associated with glycosaminoglycans and is present at the cell surface. Our detection of the plasma cell-specific antigen B-B4 (syndecan-1) on tumor cells of classical HD further supports that RS cell progenitors may be related to germinal/postgerminal center mature B cells and suggests that expression of syndecan-1 may contribute to some of the typical biologic and histopathologic features of classical HD, with a special regard to the NS subtype.

scholarly journals Reed-Sternberg Cells of Classical Hodgkin's Disease React With the Plasma Cell-Specific Monoclonal Antibody B-B4 and Express Human Syndecan-1

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3787-3794 ◽  
Author(s):  
Antonino Carbone ◽  
Annunziata Gloghini ◽  
Valter Gattei ◽  
Massimo Degan ◽  
Salvatore Improta ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Tumor Cells ◽  
Western Blotting ◽  
Plasma Cell ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Cell Phenotype ◽  
Rt Pcr ◽  
Subtype B

Abstract Although the cellular origin of Reed-Sternberg (RS) cells of classical Hodgkin's disease (HD) has been a controversial issue for many years, recent immunophenotypic and molecular studies have suggested that RS cells of a subset of classical HD cases may be related to B cells. To further define the immunophenotypic features and the differentiation stage of RS cells, a series of 56 HD samples, including both nodular lymphocyte predominance (LP) (eight cases) and classical HD (nodular sclerosis [NS], 32 cases; mixed cellularity [MC], 16 cases) with a non-T–cell phenotype, were evaluated for the immunohistochemical expression of the B-B4 antigen, a specific marker for terminally differentiated B cells. Because the cDNA of the B-B4 antigen encodes syndecan-1, a member of a family of transmembrane heparan sulfate proteoglycans thought to be involved in binding cells of the B lineage to the interstitial matrix, the B-B4 immunoreactivity was correlated with the expression of syndecan-1 in HD-derived cell lines (L428, KM-H2), as detected by both reverse transcriptase polymerase chain reaction (RT-PCR) studies and Western blotting. Our results show that B-B4 reacts with RS cells and their morphological variants of all cases of classical HD, irrespective of their antigenic phenotype (B, undetermined), albeit at a varying degree of cellular expression. Notably, a high reactivity and staining intensity for the B-B4 monoclonal antibody (MoAb) was restricted to tumor cells from NS HD. In cases of the latter subtype, B-B4 positivity was also found in sclerosis-trapped spindle cells (fibrocytes/fibroblasts). Conversely, the putative tumor cells of nodular LP HD were consistently unreactive with the B-B4 MoAb. Finally, we have demonstrated by RT-PCR, flow cytometry, and Western blotting that cultured RS cells, of B and undetermined phenotype, express syndecan-1 mRNA and produce a form of syndecan-1, recognized by the B-B4 MoAb, which is predominantly associated with glycosaminoglycans and is present at the cell surface. Our detection of the plasma cell-specific antigen B-B4 (syndecan-1) on tumor cells of classical HD further supports that RS cell progenitors may be related to germinal/postgerminal center mature B cells and suggests that expression of syndecan-1 may contribute to some of the typical biologic and histopathologic features of classical HD, with a special regard to the NS subtype.

scholarly journals Hodgkin's disease with a B-cell phenotype often shows a VDJ rearrangement and somatic mutations in the VH genes

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 708-715 ◽  
Author(s):  
J Tamaru ◽  
M Hummel ◽  
M Zemlin ◽  
B Kalvelage ◽  
H Stein
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Hodgkin's Disease ◽  
Somatic Mutations ◽  
Hodgkin’S Disease ◽  
Receptor Gene ◽  
High Sensitivity ◽  
Cell Phenotype ◽  
Igh Genes

Abstract The nature of Hodgkin and Reed-Sternberg (HRS) cells remains in question. Immunophenotypic studies favor a relation to the lymphoid lineage with the existence of B- and T-cell types. However, studies on the detection of antigen (Ag) receptor gene rearrangements provided inconsistent results. They concur in that rearranged Ig and T-cell receptor (TCR) genes are not demonstrable in most Hodgkin's disease (HD) cases. To clarify whether this is because of the insensitivity of the method of detection or a real absence of clonal Ig heavy chain (IgH) rearrangements, a polymerase chain reaction (PCR) method with high sensitivity was applied, allowing the detection of less than 50 cells with clonally rearranged IgH genes in a mixture of 100,000 germline or individually rearranged cells. In 67 cases of HD, most of those (67%) with B-Ag+ HRS cells express clonal VDJ rearrangements of the IgH gene. No cases with T-cell Ag+ HRS cells harbored detectable clonal VDJ rearrangements. Of 10 sequenced rearranged IgH genes, the VH segment of six contained considerable somatic mutations. These results suggest that the demonstrated VDJ rearrangements stem from the HRS cells themselves and that the HRS cells of cases with rearranged IgH genes are B-cell related and correspond in their differentiation stage either to naive pregerminal center B cells or (more commonly) to germinal center/postgerminal center-derived memory B cells.

scholarly journals Expression of the c-kit receptor in human lymphomas is restricted to Hodgkin's disease and CD30+ anaplastic large cell lymphomas

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 785-792 ◽  
Author(s):  
A Pinto ◽  
A Gloghini ◽  
V Gattei ◽  
D Aldinucci ◽  
V Zagonel ◽  
...  
Keyword(s):  
Lymph Node ◽  
Tumor Cells ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Large Cell ◽  
Lymphoid Cells ◽  
Receptor Protein ◽  
Cell Phenotype ◽  
Northern Blot Hybridization ◽  
Kit Receptor

Abstract The product of the proto-oncogene c-kit is a transmembrane receptor protein that plays an important role in the regulation of normal and neoplastic hematopoiesis via the interaction with its specific ligand termed stem cell factor. To examine whether c-kit product is possibly involved in the pathogenesis of human lymphomas, we analyzed the expression of the c-kit protein in neoplastic cells from a variety of lymphoid tumors by immunostaining of lymph node frozen sections with the 17F11 antibody, detecting an extracellular epitope of the c-kit receptor, and of c-kit RNA by Northern blot hybridization. Of 24 nonHodgkin's lymphomas (NHL) of B- and T-cell phenotype, none expressed immunodetectable c-kit protein that was also not evidenced in lymphoid cells of reactive lymph nodes and normal tonsils. In contrast, c-kit protein was expressed by Reed-Sternberg cells and their mononuclear variants from 11 of 21 Hodgkin's disease (HD) cases, and in tumor cells from 11 of 16 cases of CD30+ anaplastic large cell lymphoma (ALCL). c-kit specific mRNA was also detected in lymph node tissues from HD and ALCL cases but not in neoplastic tissues from NHL other than ALCL. In addition, c-kit/CD30+ tumor cells were evidenced by flow cytometry in a patient displaying massive bone marrow involvement by ALCL. With the exclusion of lymphocyte predominance cases of HD that resulted c-kit expression and the other histologic subtypes of HD or the immunologic phenotype of tumor cells (B, T, nonB-nonT) in both HD and ALCL. The highly restricted expression of the c-kit product among human lymphomas to HD and ALCL provides a further biologic link between these two closely related lymphoma entities.

scholarly journals Hodgkin's disease with a B-cell phenotype often shows a VDJ rearrangement and somatic mutations in the VH genes

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 708-715 ◽  
Author(s):  
J Tamaru ◽  
M Hummel ◽  
M Zemlin ◽  
B Kalvelage ◽  
H Stein
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Hodgkin's Disease ◽  
Somatic Mutations ◽  
Hodgkin’S Disease ◽  
Receptor Gene ◽  
High Sensitivity ◽  
Cell Phenotype ◽  
Igh Genes

The nature of Hodgkin and Reed-Sternberg (HRS) cells remains in question. Immunophenotypic studies favor a relation to the lymphoid lineage with the existence of B- and T-cell types. However, studies on the detection of antigen (Ag) receptor gene rearrangements provided inconsistent results. They concur in that rearranged Ig and T-cell receptor (TCR) genes are not demonstrable in most Hodgkin's disease (HD) cases. To clarify whether this is because of the insensitivity of the method of detection or a real absence of clonal Ig heavy chain (IgH) rearrangements, a polymerase chain reaction (PCR) method with high sensitivity was applied, allowing the detection of less than 50 cells with clonally rearranged IgH genes in a mixture of 100,000 germline or individually rearranged cells. In 67 cases of HD, most of those (67%) with B-Ag+ HRS cells express clonal VDJ rearrangements of the IgH gene. No cases with T-cell Ag+ HRS cells harbored detectable clonal VDJ rearrangements. Of 10 sequenced rearranged IgH genes, the VH segment of six contained considerable somatic mutations. These results suggest that the demonstrated VDJ rearrangements stem from the HRS cells themselves and that the HRS cells of cases with rearranged IgH genes are B-cell related and correspond in their differentiation stage either to naive pregerminal center B cells or (more commonly) to germinal center/postgerminal center-derived memory B cells.

scholarly journals Rare Occurrence of Classical Hodgkin's Disease as a T Cell Lymphoma

2000 ◽  
Vol 191 (2) ◽  
pp. 387-394 ◽  
Author(s):  
Markus Müschen ◽  
Klaus Rajewsky ◽  
Andreas Bräuninger ◽  
Audrey Sylvia Baur ◽  
Joost J. Oudejans ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Hodgkin's Disease ◽  
Cell Lymphoma ◽  
Hodgkin’S Disease ◽  
B Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cytotoxic T Cell ◽  
Cell Phenotype ◽  
Gene Rearrangements

Recent work identified Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) as clonal progeny of mature B cells. Therefore, it is generally assumed that cHD homogenously represents a B cell lymphoma. In a subset of cHD, however, H/RS cells expressing T cell–associated proteins may be candidates for alternative lineage derivation. Single H/RS cells with cytotoxic T cell phenotype were micromanipulated from three cases of cHD and analyzed by single cell polymerase chain reaction for immunoglobulin heavy (IgH) and light chain (IgL) gene rearrangements, T cell receptor (TCR)-β gene rearrangements, and germline configuration of the IgH and TCR-β loci. H/RS cells from two cases of cHD harbored clonal, somatically mutated Ig gene rearrangements, whereas TCR-β loci were in germline configuration. In contrast, H/RS cells from an additional case harbored clonal TCR-β variable/diversity/joining (VDJ) and DJ gene rearrangements, whereas the IgH locus was in germline configuration on both alleles. Thus, in two cases of cHD with H/RS cells expressing cytotoxic T cell molecules, the tumor cells are derived from mature B cells that aberrantly express T cell markers. In a third case, however, H/RS cells were derived from a T cell, demonstrating that cHD can also occur as a T cell lymphoma.

scholarly journals Expression of the c-kit receptor in human lymphomas is restricted to Hodgkin's disease and CD30+ anaplastic large cell lymphomas

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 785-792 ◽  
Author(s):  
A Pinto ◽  
A Gloghini ◽  
V Gattei ◽  
D Aldinucci ◽  
V Zagonel ◽  
...  
Keyword(s):  
Lymph Node ◽  
Tumor Cells ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Large Cell ◽  
Lymphoid Cells ◽  
Receptor Protein ◽  
Cell Phenotype ◽  
Northern Blot Hybridization ◽  
Kit Receptor

The product of the proto-oncogene c-kit is a transmembrane receptor protein that plays an important role in the regulation of normal and neoplastic hematopoiesis via the interaction with its specific ligand termed stem cell factor. To examine whether c-kit product is possibly involved in the pathogenesis of human lymphomas, we analyzed the expression of the c-kit protein in neoplastic cells from a variety of lymphoid tumors by immunostaining of lymph node frozen sections with the 17F11 antibody, detecting an extracellular epitope of the c-kit receptor, and of c-kit RNA by Northern blot hybridization. Of 24 nonHodgkin's lymphomas (NHL) of B- and T-cell phenotype, none expressed immunodetectable c-kit protein that was also not evidenced in lymphoid cells of reactive lymph nodes and normal tonsils. In contrast, c-kit protein was expressed by Reed-Sternberg cells and their mononuclear variants from 11 of 21 Hodgkin's disease (HD) cases, and in tumor cells from 11 of 16 cases of CD30+ anaplastic large cell lymphoma (ALCL). c-kit specific mRNA was also detected in lymph node tissues from HD and ALCL cases but not in neoplastic tissues from NHL other than ALCL. In addition, c-kit/CD30+ tumor cells were evidenced by flow cytometry in a patient displaying massive bone marrow involvement by ALCL. With the exclusion of lymphocyte predominance cases of HD that resulted c-kit expression and the other histologic subtypes of HD or the immunologic phenotype of tumor cells (B, T, nonB-nonT) in both HD and ALCL. The highly restricted expression of the c-kit product among human lymphomas to HD and ALCL provides a further biologic link between these two closely related lymphoma entities.

scholarly journals Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 465-471 ◽  
Author(s):  
B Falini ◽  
B Bigerna ◽  
L Pasqualucci ◽  
M Fizzotti ◽  
MF Martelli ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Hodgkin's Disease ◽  
Cd4 T Cells ◽  
Zinc Finger Protein ◽  
Hodgkin’S Disease ◽  
Malignant Cell ◽  
Germinal Center B Cells

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.

scholarly journals A shared gene expression signature in mouse models of EBV-associated and non–EBV-associated Burkitt lymphoma

Blood ◽  
2011 ◽  
Vol 118 (26) ◽  
pp. 6849-6859 ◽  
Author(s):  
Kathryn T. Bieging ◽  
Kamonwan Fish ◽  
Subbarao Bondada ◽  
Richard Longnecker
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Mouse Model ◽  
Tumor Cells ◽  
Burkitt Lymphoma ◽  
Gene Expression Signature ◽  
Differentially Expressed ◽  
Cell Phenotype ◽  
Phenotypic Differences ◽  
Tumor Onset

AbstractThe link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional profiles of tumor cells from LMP2A/λ-MYC and λ-MYC mice are strikingly similar, with fewer than 20 genes differentially expressed. We evaluated the functional significance of one of the most interesting differentially expressed genes, Egr1, and found that it was not required for acceleration of tumor onset by LMP2A. Our studies demonstrate the remarkable ability of LMP2A to affect the pretumor B-cell phenotype and tumorigenesis without substantially altering gene expression in tumor cells.

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