Lack of Hcv Infection in Malignant, Cells Refutes the Hypothesis of a Direct Transforming Action of the Virus in the Pathogenesis of Hcv-Associated B-Cell Nhls

Aims and background Preliminary evidence suggests that hepatitis C virus (HCV) might play a pathogenetic role in autoimmune-related, non-malignant B-cell lymphoproliferation, as well as in a subset of B-cell non-Hodgkin's lymphomas (NHLs). With regard to the mechanism(s) by which HCV might favor B-cell expansion and malignant transformation, most data support an indirect pathogenetic role of the virus as an exogenous trigger. A direct oncogenetic role of HCV by direct cell infection and deregulation has only been hypothesized on the basis of the lymphotropism of the virus. Methods In this study we investigated the possible HCV infection of NHL B cells by means of sensitive and quantitative polymerase chain reaction (PCR) on affinity-purified neoplastic cells, and by HCV-specific immunohistochemistry and in situ hybridization. Results HCV infection of neoplastic B cells was documented in only three cases, namely the low-grade B-cell NHLs that arose in the course of mixed cryoglobulinemia syndrome (MC). HCV infection, below one viral genome per cell, was detectable only by PCR. All the remaining low-grade (one case) and high-grade B-cell NHLs (two cases) were HCV uninfected. Previous immunoglobulin gene analyses were consistent with an antigen-driven B-cell lymphoproliferation in the studied cases. Conclusions Overall, our data are consistent with an indirect oncogenetic role of HCV in B-cell lymphomagenesis as an exogenous trigger. Infection of B cells by HCV appears possible in some NHL subsets, but the implications remain unknown.

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Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas

Blood ◽

10.1182/blood.v88.1.222.222 ◽

1996 ◽

Vol 88 (1) ◽

pp. 222-229 ◽

Cited By ~ 111

Author(s):

KF Norrback ◽

K Dahlenborg ◽

R Carlsson ◽

G Roos

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Telomerase Activity ◽

Lymphoid Tissues ◽

Low Grade ◽

Malignant Lymphomas ◽

Hodgkin's Lymphomas ◽

Germinal Center B Cells

Abstract Activation of telomerase seems to be a prerequisite for immortalization and is found in permanent cell lines and most malignant tumors. Normal somatic cells are generally telomerase negative, except for bone marrow stem cells. Weak activity is also present in peripheral blood cells. In the present study strong telomerase activity was demonstrated in vivo in normal mature cells of the immune system, as well as in malignant lymphomas. Benign lymph nodes had lower telomerase activity than benign tonsils, which exhibited intermediate to high activity comparable with findings in malignant lymphomas. In benign tonsils the activity seemed to be restricted to germinal center B cells. In benign lymphoid tissues telomerase activity correlated with B-cell numbers and cell proliferation, but this was not observed in the lymphoma group. High- grade lymphomas exhibited higher levels of telomerase compared with low- grade cases. The data showed that in vivo activation of telomerase is a characteristic feature of germinal center B cells. Different signals for activation of telomerase are likely to exist, one of them being immune stimulation. The data suggest that telomerase activity in malignant lymphomas can be explained by an “induction and retention” model, ie, transformation occurs in a normal, mature B cell with reactivated telomerase, which is retained in the neoplastic clone.

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Expression and release of CD27 in human B-cell malignancies

Blood ◽

10.1182/blood.v82.11.3430.3430 ◽

1993 ◽

Vol 82 (11) ◽

pp. 3430-3436 ◽

Cited By ~ 84

Author(s):

MH van Oers ◽

ST Pals ◽

LM Evers ◽

CE van der Schoot ◽

G Koopman ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Peripheral Blood ◽

Growth Factor Receptor ◽

Lymphocytic Leukemia ◽

Enzyme Linked Immunosorbent Assay ◽

Low Grade ◽

B Cell Malignancies ◽

Variable Intensity ◽

Hodgkin's Lymphomas

Abstract CD27, a transmembrane disulfide-linked 55-kD homodimer, belongs to the nerve growth factor-receptor family, a group of homologous molecules involved in lymphocyte differentiation and selection. It is expressed on mature thymocytes, peripheral blood T cells, and a subpopulation of B cells. We investigated the expression of CD27 on malignant B cells representative for a broad range of stages in physiologic antigen- independent and -dependent B-cell development. In normal lymphoid tissue CD27+ B cells were only found in the peripheral blood (29.8% +/- 10.8%, n = 13) and in germinal centers. With the exception of pro-B and the majority of pre-pre-B acute lymphocytic leukemias and of myelomas, CD27 expression of variable intensity was detected on almost all immature and mature malignant B cells tested. Moreover, using a sandwich enzyme-linked immunosorbent assay we could show the presence of sometimes very high (up to 6,000 U/mL; normal values < 190 U/mL) amounts of the soluble 28- to 32-kD form of CD27 (sCD27) in the sera of patients with B-cell malignancies. The highest levels of sCD27 were observed in patients with chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphomas. Most importantly, both in transversal and longitudinal studies, we found a strong correlation between sCD27 levels in the serum and tumor load, indicating that sCD27 can be used as a disease-marker in patients with acute and chronic B-cell malignancies.

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Hepatitis C Virus Infection and B-Cell Non-Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v106.11.4668.4668 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4668-4668

Author(s):

Janet G. Grudeva

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Hcv Infection ◽

Control Group ◽

Cell Infection ◽

Serum Samples ◽

Pathogenetic Role ◽

Significant Difference

Backgroud: An increasing number of bacterial and viral infections have been linked with specific subtypes of lymphoma. Preliminary evidence suggests that hepatitis C virus (HCV) might play a pathogenetic role in autoimmune-related, non-malignant B-cell lymphoproliferation, as well as a subset of B-cell non-Hodgkin, s lymphomas (B-NHL), often with extranodal localization. Design and methods: The study was conducted in the Department of Hematology and consisted 149 (86 male, 63 female) untreated patients with a new diagnosis of B-NHL for 5-years period (2000–2004). HCV infection was investigated by testing for HCV antibodies in serum samples. The controls were 587 patients (without intravenous drug users) in other departments of the same hospital. Results: HCV infection was documented in 13 cases (8,4%) with NHL. The infected patients were not clinically relevant cryoglobulinemic activity, increased rate of autoimmune disorders and extranodal localizations prevalence. There was statistically significant difference between the NHL and control group (p<0,01) and no statistically significant difference between man/women carriers (p>0,05) into the NHL group. Overall, the clinical outcome of HCV-positive NHL does not seem to be different from that of NHL patients without HCV infection. However, the evidence of a significant liver injury may predict a worse prognosis in these cases. Conclusions: Our date suggest that HCV infection may be associated with B-NHL. With regard to the mechanism(s) by which HCV might favor B-cell expansion and malignant transformation, most date support an indirect pathogenetic role of the virus as an exogenous trigger. A direct oncogenetic role of HCV by direct cell infection and deregulation has only been hypothesized on the basis of the lymphotropism of the virus.

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HCV Infection and B-Cell Lymphomagenesis

Advances in Hematology ◽

10.1155/2011/835314 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Masahiko Ito ◽

Hideki Kusunoki ◽

Keiko Mochida ◽

Kazunari Yamaguchi ◽

Toshiaki Mizuochi

Keyword(s):

B Cells ◽

B Cell ◽

Chronic Infection ◽

Recent Literature ◽

Epidemiological Data ◽

Mixed Cryoglobulinemia ◽

Hcv Infection ◽

Chronic Hcv Infection ◽

Chronic Hcv

Hepatitis C virus (HCV) has been recognized as a major cause of chronic liver diseases worldwide. It has been suggested that HCV infects not only hepatocytes but also mononuclear lymphocytes including B cells that express the CD81 molecule, a putative HCV receptor. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkin's lymphoma (NHL). Epidemiological data indicate an association between HCV chronic infection and the occurrence of B-cell NHL, suggesting that chronic HCV infection is associated at least in part with B-cell lymphomagenesis. In this paper, we aim to provide an overview of recent literature, including our own, to elucidate a possible role of HCV chronic infection in B-cell lymphomagenesis.

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Role of Anti-Hepatitis C Virus (HCV) Treatment in HCV-Related, Low-Grade, B-Cell, Non-Hodgkin's Lymphoma: A Multicenter Italian Experience

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.008 ◽

2005 ◽

Vol 23 (3) ◽

pp. 468-473 ◽

Cited By ~ 174

Author(s):

Daniele Vallisa ◽

Patrizia Bernuzzi ◽

Luca Arcaini ◽

Stefano Sacchi ◽

Vittorio Callea ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Antiviral Treatment ◽

Complete Response ◽

Hcv Infection ◽

Low Grade ◽

Hcv Treatment ◽

Hematologic Response

Purpose Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. Patients and Methods Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. Results Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 ± 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. Conclusion This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

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Bone marrow origin of a B-cell lymphoma

Blood ◽

10.1182/blood.v72.1.94.bloodjournal72194 ◽

1988 ◽

Vol 72 (1) ◽

pp. 94-101

Author(s):

LF Bertoli ◽

H Kubagawa ◽

GV Borzillo ◽

PD Burrows ◽

MT Schreeder ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

Variable Region ◽

B Cell Lymphoma ◽

Large Cell ◽

Low Grade ◽

Immunoglobulin Gene ◽

B Lineage

To search for precursors of the neoplastic B cells in a patient with a nodular lymphoma, we produced a monoclonal antibody to a variable region idiotope on the lymphoma IgM heavy chain. Clonal ancestors of the lymphoma cells were identified by this marker among bone marrow pre- B cells (5% to 26%). A second antiidiotype (anti-Id) antibody specific for the complete lymphoma IgM kappa recognized 10% of B cells in bone marrow and blood and greater than 95% of B cells in lymphomatous lymph nodes, including one obtained after tumor conversion to a diffuse large cell lymphoma. Immunoglobulin gene analysis surprisingly revealed expansion of multiple clones of early B lineage cells in bone marrow, including members of the neoplastic clone. The data suggest that this lymphoma arose through a progression of transformational events beginning in bone marrow: first, creation of an oligoclonal pre- neoplastic pool of pre-B cells, subsequent conversion of a single subclone into low grade neoplastic B cells that homed to the lymph node follicles, and later progression to a more invasive form of the B-cell lymphoma.

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The BLyS Survival Pathway in NHL-B Cells: Constitutive NF-kB and NFAT Lead to Activation.

Blood ◽

10.1182/blood.v104.11.2279.2279 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2279-2279

Author(s):

Lingchen Fu ◽

Tamayo Archito ◽

Yen-Chiu Lin-Lee ◽

Lan Pham ◽

Linda Yoshimura ◽

...

Keyword(s):

Flow Cytometry ◽

B Cells ◽

B Cell ◽

Cell Lines ◽

Low Grade ◽

Rt Pcr ◽

Protein Levels ◽

Realtime Pcr ◽

Survival Pathway ◽

Hodgkin's Lymphomas

Abstract B-cell non-Hodgkin’s Lymphomas (NHL-B), neoplasms of the immune system have shown a significant increase in incidence in the USA over the last three decades. While the pathophysiology of the NHL-B is still unclear, the need to identify the relevant genes and critical signaling pathways, and their involvement in the disease processes in NHL-B have begun to be elucidated. Recently, B Lymphocyte Stimulator (BLyS) has been described as a relatively new member of the TNF ligand family, as a potent cell survival factor that is expressed in many hematopoietic cells, including neoplastic B cells. BLyS can bind to three receptors: TACI, BCMA, BAFF-R, and plays a critical role in B cell maturation, differentiation and proliferation. Relatively high levels of BLyS has been found in the serum of NHL-B patients as well as of the patients with autoimmune disease. The mechanisms of BLyS gene expression and regulation is still unclear, but we have recently found that BLyS is constitutively expressed in several NHL-B cell lines and patient tumor samples by RT-PCR, confocal microscopy, realtime PCR and flow cytometry (FCM). We detected high levels and differential expression of BLyS receptors (TACI, BCMA, BAFF-R) in several NHL-B cell lines by flow cytometry, RT-PCR and realtime PCR in both NHL-B cell lines and patient tumor samples. We have identified a single binding site for NF-kB and two binding sites for NFAT in the BLyS promoter. We also show in aggressive lymphoma B cells that constitutive NF-kB and NFAT binds to the BLyS promoter constitutively. Inhibiting NF-kB/NFAT activity levels, using the NF-kB inhibitors, BAY-11 or Velcade (PS-341), can decrease NF-kB binding activity in the BLyS promotor by EMSA. These inhibitors also decrease BLyS and BAFF-R mRNA and protein levels by realtime PCR and flow cytometry. Similarly, when NHL-B cells were transfected with dominant negative NFAT or NF-kB constructs, there is a 50% decrease in BLyS and BAFF-R expressions, demonstrating that both the ligand (BLyS) and the receptor (BAFF-R) expression are regulated by NFAT and NF-kB. Interestingly, follicular (low grade) lymphoma cells do not express constitutive NF-kB/NFAT activation, and barely detectable mRNA and protein levels of BlyS, but can be activated with exogenous CD154/anti IgM in vitro, activating NF-kB/NFAT and promoting binding to the BLyS promoter by EMSA. This results in a significant increase of BLyS protein level by flow cytometry. Our studies indicate that constitutive NF-kB and NFAT are critical transcriptional regulators of the BLyS survival pathway in malignant B cells that may provide a future therapeutic target in the aggressive NHL-B.

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Histological Characteristics Of Hepatitis C-Associated B-Cell Non-Hodgkin Lymphomas. Results Of The French Lympho-C ANRS HC-13 Multicentric Study Of 133 Patients

Blood ◽

10.1182/blood.v122.21.3005.3005 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3005-3005

Author(s):

Danielle Canioni ◽

Jean Marie Michot ◽

Catherine Settegrana ◽

Henda Driss ◽

Pascaline Rabiega ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

De Novo ◽

Hcv Infection ◽

Antigenic Stimulation ◽

Low Grade ◽

Multicentric Study ◽

Chronic Antigenic Stimulation ◽

Follicular Lymphomas

Abstract Introduction HCV infection is associated with the development of B-cell non Hodgkin lymphomas (NHL), preferentially of marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL) subtypes. Other subtypes of B-cell NHL are rare. HCV-related lymphomagenesis may constitute in some cases a model of lymphoma induced by chronic antigenic stimulation. Moreover, a direct role of an infection of B cells by HCV is also an alternative hypothesis. We performed a multicentric observational study of HCV-related B-cell NHL in France in order to study the real distribution of their histological subtypes and their correlation with in situ expression of HCV virus. Patients & Methods Adult patients with B-NHL and active HCV infection were included in an observational multicentric study with the exclusion of those who were co-infected with HIV. Data were collected from patients with either ongoing or past history of HCV infection. Cytological and histological samples were collected for centralized review and molecular analyses. A large panel of antibodies was performed on each sample for subtyping the B-cell NHL and HCV-NS3 antibody immunostaining was made each time we had enough material. Results Between 2006 and 2012, 133 consecutive patients were enrolled in 26 French hospitals, among them 17 patients were excluded from analysis. At lymphoma diagnosis the median age was 61 years and the gender M/F ratio was 1. Histological samples of 81/116 patients were reviewed by a panel of expert hematopathologists. The most frequent B-cell NHL subtype was DLBCL in 30/81 patients (37.5%) among them 14/30 (46.6%) were transformed from underlying low grade B-cell NHL. For 26/30 DLBCL we had enough material for performing Hans score: 18 (69%) were of non germinal center (GC) origin and 8 (31%) of GC origin. Interestingly, most de novo DLBCL were of non GC subtype (92%) whereas in transformed DLBCL 50% were of non GC subtype. MZL represent 22/81 cases (27%), 8/81 (9.9%) were follicular lymphomas and other small B-NHL subtypes represent the other cases. Patients with DLBCL displayed frequent extra-nodal involvement (digestive tract, liver) (60%) and those with MZL had the highest proportion (73%) of extranodal localisations (spleen, bone marrow, blood, eye) whereas follicular lymphomas were mainly developed in lymph nodes. Twenty-nine cases could be tested for HCV NS3 antibody, 26 exhibited evaluable staining: 12 B-NHL had in situ positive staining (most of them were DLBCL (67%) with a slight predominance of transformed DLBCL compared to de novo (62%) and 14 had negative staining (most of them were MZL or other small B-cell NHL (92%). Conclusion This study underlines the heterogeneity of HCV-related B-cell NHL with a majority of extra-nodal localizations of these lymphomas, a predominance of DLBCL and MZL and a high proportion of DLBCL developed on low grade B-NHL comparing to de novo DLBCL. We found a different GC/non GC repartition between de novo versus transformed DLBCL with a higher proportion of GC versus non GC in transformed DLBCL than in de novo DLBCL. In situ HCV virus expression was more frequently observed in DLBCL than in other subtypes of B-NHL which could indicate that the growth and development of lymphoma cells may be associated with the presence of HCV infection of B cells. Therefore, we postulate that the B cell transformation is linked with chronic antigenic stimulation in MZL and to direct infection in DLBCL. It might also explain that virological success seems to improve prognosis preferentially in MZL subtype in our series. Disclosures: Haioun: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Bone marrow origin of a B-cell lymphoma

Blood ◽

10.1182/blood.v72.1.94.94 ◽

1988 ◽

Vol 72 (1) ◽

pp. 94-101 ◽

Cited By ~ 25

Author(s):

LF Bertoli ◽

H Kubagawa ◽

GV Borzillo ◽

PD Burrows ◽

MT Schreeder ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

Variable Region ◽

B Cell Lymphoma ◽

Large Cell ◽

Low Grade ◽

Immunoglobulin Gene ◽

B Lineage

Abstract To search for precursors of the neoplastic B cells in a patient with a nodular lymphoma, we produced a monoclonal antibody to a variable region idiotope on the lymphoma IgM heavy chain. Clonal ancestors of the lymphoma cells were identified by this marker among bone marrow pre- B cells (5% to 26%). A second antiidiotype (anti-Id) antibody specific for the complete lymphoma IgM kappa recognized 10% of B cells in bone marrow and blood and greater than 95% of B cells in lymphomatous lymph nodes, including one obtained after tumor conversion to a diffuse large cell lymphoma. Immunoglobulin gene analysis surprisingly revealed expansion of multiple clones of early B lineage cells in bone marrow, including members of the neoplastic clone. The data suggest that this lymphoma arose through a progression of transformational events beginning in bone marrow: first, creation of an oligoclonal pre- neoplastic pool of pre-B cells, subsequent conversion of a single subclone into low grade neoplastic B cells that homed to the lymph node follicles, and later progression to a more invasive form of the B-cell lymphoma.

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