scholarly journals Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin's disease cell lines

Blood ◽  
1995 ◽  
Vol 85 (3) ◽  
pp. 780-789 ◽  
Author(s):  
A Carbone ◽  
A Gloghini ◽  
V Gattei ◽  
D Aldinucci ◽  
M Degan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Lines ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Growth Factor Receptor ◽  
Large Cell ◽  
Distinct Pattern ◽  
Histologic Subtype ◽  
Hodgkin's Lymphomas

CD40 is a member of the nerve growth factor receptor family, showing a significant homology to the Hodgkin's disease (HD)-associated antigen CD30 and is capable of transduce growth signals in a number of cell types. A series of 312 lymphoma samples, including 139 cases of HD, 32 cases of CD30+ anaplastic large cell (ALC) lymphomas, 141 cases of other non-Hodgkin's lymphomas (NHLs), and a panel of HD- or NHL-derived cell lines, were evaluated for CD40 expression by immunostaining of paraffin embedded sections, cell smears and flow cytometry. CD40 was strongly expressed with a highly distinct pattern of staining on Reed- Sternberg (RS) cells and variants in 100% (139/139) of HD cases, irrespective of their antigenic phenotype (T, B, non T-non B) and histologic subtype of HD. Conversely, CD40 was immunodetected on only one third (12/32; 37%) of ALC lymphoma cases and on 105 of 127 B-cell NHLs. The relative cell density of CD40 on HD cell lines (L-428, KM-H2, HDLM-2) as assessed by flow cytometry was significantly higher than on all other lymphoma cells analyzed. Engagement of CD40 by its soluble ligand (CD40L) enhanced both clonogenic capacity and colony cell survival of HD cell lines. Such effect was potentiated by interleukin-9 costimulation in KM-H2 cells. Finally, we have shown that in vitro rosetting of activated CD4+ T cells to HD cells (L-428) is mediated in part by the CD40/CD40L adhesion pathway. Our data indicate that CD40 is a useful antigen for immunodetection and identification of tumor cells in all subtypes of HD, and suggest that it may play a role in the regulation of RS cell expansion and the contact-dependent interactions of these cells with cytokine-producing T lymphocytes.

scholarly journals ALK gene products in anaplastic large cell lymphomas and Hodgkin's disease

Blood ◽  
1995 ◽  
Vol 86 (5) ◽  
pp. 1694-1700 ◽  
Author(s):  
H Herbst ◽  
J Anagnostopoulos ◽  
B Heinze ◽  
H Durkop ◽  
M Hummel ◽  
...  
Keyword(s):  
Cell Lines ◽  
Hodgkin's Disease ◽  
Fusion Gene ◽  
Hodgkin’S Disease ◽  
Young Patients ◽  
Large Cell ◽  
Common Type ◽  
Gene Products ◽  
Cytogenetic Analyses

The translocation t(2;5)(p23;q35), discovered in CD30+ anaplastic large cell (ALC) lymphomas, creates a potentially oncogenic fusion gene, part of which is contributed by a novel tyrosine kinase, ALK. Absence of ALK expression from normal hematolymphoid cells provides a basis for the morphologic assessment of t(2;5). The distribution of the t(2;5) in ALC lymphomas and Hodgkin's disease (HD), as assayed by nonmorphologic methods, is controversial. We used in situ hybridization and/or immunohistology to show ALK gene products in 85 ALC lymphomas, 82 HD cases, 40 other lymphoproliferations, as well as in 6 HD- and 4 ALC lymphoma-derived cell lines. ALK gene products were restricted to t(2;5)-positive ALC lymphoma cell lines and tumor cells of 16 primary non-B cell, common-type ALC lymphomas. These were mainly from young patients with initial lymphonodal disease. ALK expression was not detectable in any other specimen, including all cases of HD and HD-like type ALC lymphoma as well as secondary ALC lymphomas. Full congruence was noted for labeling results obtained with both methods. In agreement with cytogenetic analyses, but at variance with recently published studies, ALK gene expression distinguishes a subset of ALC lymphomas from other CD30+ lymphomas, including HD. The results do not support concepts attributing a significant role to the t(2;5) in the development of HD.

scholarly journals Absence of the t(2;5) in Hodgkin's disease [see comments]

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2845-2847 ◽  
Author(s):  
LM Weiss ◽  
JR Lopategui ◽  
LH Sun ◽  
OW Kamel ◽  
CH Koo ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Blot Hybridization ◽  
Southern Blot Hybridization ◽  
Large Cell ◽  
Common Finding ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Hodgkin's Lymphomas

The cytogenetics of Hodgkin's disease (HD) is poorly understood. However, a t(2;5) is a common finding in CD30+ anaplastic large cell lymphoma (ALCL), a neoplasm thought by some to be closely related to HD. Recently, the t(2;5) has been cloned and found to represent fusion of the NPM gene with the ALK gene. Using Southern blot hybridization, one group has reported finding rearrangements of NPM in a proportion of cases of both ALCL and HD. In the current study, we used a highly sensitive reverse transcriptase-polymerase chain reaction methodology to analyze 34 cases of HD for the t(2;5). We were unable to find polymerase chain reaction evidence for the t(2;5) in any of the cases of HD, a result significantly different from our previous study of CD30+ non-Hodgkin's lymphomas (P < .02) including ALCL (P < .04), using identical methods. Our results do not support the hypothesis that the t(2;5) represents a common chromosomal abnormality for both HD and ALCL.

Preclinical Activity of Brentuximab Vedotin (SGN-35) in Primary Effusion Lymphoma (PEL),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3728-3728 ◽  
Author(s):  
Shruti Bhatt ◽  
Brittany Ashlock ◽  
Yaso Natkunam ◽  
Juan Carlos Ramos ◽  
Enrique Mesri ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Primary Effusion Lymphoma ◽  
Large Cell ◽  
Brentuximab Vedotin ◽  
Antibody Drug Conjugate ◽  
Human Herpes Virus 8

Abstract Abstract 3728 Primary effusion lymphoma (PEL) is a distinct and aggressive subtype of non-Hodgkin lymphoma (NHL) commonly presenting with pleural, peritoneal, or pericardial malignant effusions usually without a contiguous tumor mass. PEL is most commonly diagnosed in HIV-positive patients, accounting for 4% of all NHLs in this population, yet may also develop in immunosuppressed HIV-negative individuals. While Human Herpes Virus 8 (HHV8 or Kaposi's sarcoma-associated herpesvirus) is directly implicated in the oncogenesis of this lymphoma, most PEL cases are also associated with Epstein-Barr virus and the combination of the two may facilitate transformation. The tumor cells exhibit plasmablastic features and express CD45, CD38, CD138, HHV8 and CD30. PEL is an aggressive tumor characterized by a short median survival of only 6 months with current therapeutic approaches underscoring the urgent need for development of new therapeutics. Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) comprised of an anti-CD30 monoclonal antibody cAC10 conjugated by a protease-cleavable dipeptide linker to a potent cell killing agent monomethyl auristatin E (MMAE). Following binding to CD30, brentuximab vedotin is rapidly internalized and is transported to lysosomes, where the peptide linker is selectively cleaved allowing binding of the released MMAE to tubulin and leading to cell cycle arrest and apoptosis. Brentuximab vedotin was recently reported to have promising antitumor activity in CD30 expressing tumors, such as Hodgkin and Anaplastic large cell lymphomas. Since PEL tumors are reported to express CD30, we have hypothesized that brentuximab vedotin might be effective in the treatment of this NHL subtype. Initially, we have confirmed by flow cytometry the expression of CD30 on PEL cell lines (UM-PEL 1, UM-PEL 3, BC-1 and BC-3), and by review of immunohistochemistry and flow cytometry results in patients with previous diagnosis of PEL at our institution. To examine in vitro potency of brentuximab vedotin, UM-PEL 1, UM-PEL 3, BC-1 and BC-3 PEL cell lines were treated with brentuximab vedotin at concentration ranging from 0–100 micrograms/ml. Staining with YO-PRO and Propidium Iodide (PI) demonstrated dose dependent cell apoptosis and death in all the cell lines at 72 hours post treatment. In contrast, control IgG conjugated with MMAE failed to induce apoptosis and cell death of PEL cell lines confirming specific brentuximab vedotin cytotoxicity. Furthermore, brentuximab vedotin decreased proliferation of PEL cells at 48 hours leading to a complete proliferation arrest at 72 hours, as measured by MTS assay. These effects were absent after equivalent doses of control IgG conjugated drug treatment. Supportive to this, labeling of cells with PI to detect active DNA content by flow cytometry showed that bretuximab vedotin induced growth arrest in G2/M phase. To further establish the anti-tumor potential of brentuximab vedotin in vivo, we used the direct xenograft UM-PEL 1 model, established in our laboratory (Sarosiek, PNAS 2010), which mimics human PEL tumors. UM-PEL 1 bearing mice were injected intraperitoneally 3 times a week with brentuximab vedotin or control IgG conjugated MMAE for 4 weeks. Brentuximab vedotin treatment markedly prolonged overall survival of UM-PEL-1 bearing mice compared to controls (p Disclosures: No relevant conflicts of interest to declare.

Telomerase Activity in Hodgkin's Disease

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 567-573 ◽  
Author(s):  
Karl-Fredrik Norrback ◽  
Gunilla Enblad ◽  
Martin Erlanson ◽  
Christer Sundström ◽  
Göran Roos
Keyword(s):  
Cell Lines ◽  
Hodgkin's Disease ◽  
Malignant Tumors ◽  
Hodgkin’S Disease ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Cationic Protein ◽  
Considerable Impact ◽  
Hodgkin's Lymphomas

Telomere maintenance executed by the action of telomerase seems to be a prerequisite for immortalization. Telomerase is found in most cell lines and malignant tumors. A telomerase-independent mechanism for telomere maintenance in Hodgkin's disease has been proposed in the absence of detectable telomerase activity. In this study, telomerase activity was detected in 31 of 77 Hodgkin's disease samples and a strong correlation between eosinophilia and absence of detectable telomerase activity was found. Purified eosinophils and specifically eosinophil-derived neurotoxin and eosinophilic cationic protein, both ribonucleases, were found to degrade telomerase. Purified neutrophils also exhibited weak telomerase degradative activity. Reanalysis of previously telomerase-negative Hodgkin's disease samples with eosinophilia using ribonuclease inhibitors resulted in the detection of telomerase activity. Ribonuclease-containing cells in vivo thus have a considerable impact on the detectability of telomerase. In Hodgkin's disease samples without eosinophilia, 24 of 27 exhibited telomerase activity at decreased levels compared with non-Hodgkin's lymphomas and at increased levels compared with reactive nodes indicative of a telomerase positive tumor component in Hodgkin's disease. Telomerase positivity of the Hodgkin's and Reed-Sternberg cells in vivo was also supported by high levels of telomerase expression in Hodgkin's disease cell lines. Based on our data, Hodgkin's lymphomas are potential targets for antitelomerase therapy.

scholarly journals Amplification of genomic DNA demonstrates the presence of the t(2;5) (p23;q35) in anaplastic large cell lymphoma, but not in other non- Hodgkin's lymphomas, Hodgkin's disease, or lymphomatoid papulosis

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1771-1779 ◽  
Author(s):  
AH Sarris ◽  
R Luthra ◽  
V Papadimitracopoulou ◽  
M Waasdorp ◽  
MA Dimopoulos ◽  
...  
Keyword(s):  
Anaplastic Large Cell Lymphoma ◽  
Hodgkin's Disease ◽  
Genomic Dna ◽  
Cell Lymphoma ◽  
Hodgkin’S Disease ◽  
Large Cell ◽  
Lymphomatoid Papulosis ◽  
Large Cell Lymphoma ◽  
Hodgkin's Lymphomas ◽  
Dna Pcr

Anaplastic large cell lymphoma (ALCL) is a distinct clinicopathologic variant of intermediate grade non-Hodgkin's lymphomas (NHL) composed of large pleomorphic cells that usually express the CD30 antigen and interleukin (IL)-2 receptors, and is characterized by frequent cutaneous and extranodal involvement. With variable frequency ALCL bear the t(2;5)(p23;q35) chromosomal translocation that fuses the nucleophosmin (NPM) gene on chromosome 5q35 to a novel protein kinase gene, Anaplastic Lymphoma Kinase (ALK), on chromosome 2p23. We determined the frequency of this translocation with a novel DNA polymerase chain reaction (PCR) technique using 0.5 microgram of genomic DNA, 5′-primers derived from the NPM gene and 3′-primers derived from the ALK gene and hybridization with internal probes. The presence of amplifiable DNA in the samples was tested with the inclusion in the PCR reaction of oligonucleotide primers designed to amplify a 3016-bp fragment from the beta-globin locus. NMP-ALK fusion amplicons were detected using DNA isolated either from all three ALCL cell lines tested, or from all four primary ALCL tumors known to contain the t(2;5)(p23;q35) translocation. Nested amplicons were detected by hybridization in 100% of specimens diluted 10(4)-fold and in 20% of those diluted 10(5)-fold. We subsequently examined archival genomic DNA from 20 patients with ALCL, 39 with diffuse large cell, 2 with mantle cell, 20 with peripheral T cell, 13 with low-grade NHL, 31 with Hodgkin's disease (HD), and 6 with lymphomatoid papulosis. Fusion of the NPM and ALK genes was detected in three of 18 patients with ALCL who had amplifiable DNA (17%, 95% confidence intervals 4% to 41%), but not in any patients with other NHL, HD, or lymphomatoid papulosis. The amplicon sizes were different in all cell lines and patients reflecting unique genomic DNA breakpoints. We conclude that with genomic DNA-PCR the rearrangement of the NPM and ALK loci is restricted to patients with ALCL. Further studies are needed to determine the prognostic significance of the NPM-ALK rearrangement, to determine whether its detection can aid in the differential diagnosis between ALCL. Hodgkin's disease, and lymphomatoid papulosis, and to establish the usefulness of the genomic DNA PCR in the monitoring of minimal residual disease in those patients whose tumors bear the t(2;5).

scholarly journals Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1311-1317 ◽  
Author(s):  
H Merz ◽  
FA Houssiau ◽  
K Orscheschek ◽  
JC Renauld ◽  
A Fliedner ◽  
...  
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
Cell Lines ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Large Cell ◽  
Anaplastic Lymphoma ◽  
T Cell Lymphomas ◽  
Interleukin 9 ◽  
Unique Association

To test the possibility that interleukin-9 (IL-9), the human homologue of the mouse T-cell growth factor P40, may be involved in the pathogenesis of human lymphomas, we examined IL-9 expression in a variety of tumors both by Northern blot analysis and by in situ hybridization. Of 18 B-cell non-Hodgkin's lymphomas and 11 peripheral T- cell lymphomas, none expressed IL-9 message. By contrast, IL-9 message was found in two of six cases of large cell anaplastic lymphoma (LCAL) and in 6 of 13 cases of Hodgkin's disease (HD). In HD the strongest signals were observed in Hodgkin (H) and Sternberg-Reed (SR) cells, but IL-9 mRNA was also detected in small lymphocytic cells. A search for IL- 9 message in a panel of 20 cell lines derived both from hematopoietic and nonhematopoietic tumors confirmed the unique association of IL-9 expression with HD and LCAL in as much as the only two cell lines with IL-9 message were derived from cases of HD and LCAL. These results suggest that IL-9 is not involved as an autocrine growth factor in the pathogenesis of most B- and T-cell lymphomas, but that it may play a role in HD and LCAL.

Telomerase Activity in Hodgkin's Disease

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 567-573 ◽  
Author(s):  
Karl-Fredrik Norrback ◽  
Gunilla Enblad ◽  
Martin Erlanson ◽  
Christer Sundström ◽  
Göran Roos
Keyword(s):  
Cell Lines ◽  
Hodgkin's Disease ◽  
Malignant Tumors ◽  
Hodgkin’S Disease ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Cationic Protein ◽  
Considerable Impact ◽  
Hodgkin's Lymphomas

Abstract Telomere maintenance executed by the action of telomerase seems to be a prerequisite for immortalization. Telomerase is found in most cell lines and malignant tumors. A telomerase-independent mechanism for telomere maintenance in Hodgkin's disease has been proposed in the absence of detectable telomerase activity. In this study, telomerase activity was detected in 31 of 77 Hodgkin's disease samples and a strong correlation between eosinophilia and absence of detectable telomerase activity was found. Purified eosinophils and specifically eosinophil-derived neurotoxin and eosinophilic cationic protein, both ribonucleases, were found to degrade telomerase. Purified neutrophils also exhibited weak telomerase degradative activity. Reanalysis of previously telomerase-negative Hodgkin's disease samples with eosinophilia using ribonuclease inhibitors resulted in the detection of telomerase activity. Ribonuclease-containing cells in vivo thus have a considerable impact on the detectability of telomerase. In Hodgkin's disease samples without eosinophilia, 24 of 27 exhibited telomerase activity at decreased levels compared with non-Hodgkin's lymphomas and at increased levels compared with reactive nodes indicative of a telomerase positive tumor component in Hodgkin's disease. Telomerase positivity of the Hodgkin's and Reed-Sternberg cells in vivo was also supported by high levels of telomerase expression in Hodgkin's disease cell lines. Based on our data, Hodgkin's lymphomas are potential targets for antitelomerase therapy.

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