Exposure to animals and increased risk of marginal zone B-cell lymphomas of the ocular adnexae.

BACKGROUND: Ocular adnexal marginal zone B-cell lymphoma (OAMZL) has been associated with Chlamydophila psittaci, an infection that may be transmitted by carrier animals. However, it is still unclear whether exposure to animals affects the risk of OAMZL in comparison with other lymphoma histotypes. We therefore investigated the role of professional and/or domestic exposures to animals in the occurrence of OAMZL, as compared with other types of lymphoma. METHODS: A hospital-based case-control study was carried out on 43 consecutive OAMZL patients (cases) and 87 consecutive patients with nodal non-Hodgkin's lymphomas (NHLs; controls). Multiple logistic regression (MLR) odds ratios (ORs), and 95% confidence intervals (CIs) were used to estimate the association between exposures to animals and OAMZL risk. RESULTS: A higher proportion of cases reported a lifetime exposure to household animals (79.1% vs 64.4% among controls), with a non-statistical significant MLR-OR of 2.18 (95% CI: 0.85-5.62). The OAMZL cases more frequently reported a history of occupation in breeding and/or slaughtering than controls (34.9% vs 6.9%), with an overall increased risk of 7.69 (95%CI: 2.65-22.34). CONCLUSION: These results indicate that, compared with nodal NHLs, the risk of OAMZL is markedly increased by contact with animals, particularly by occupational exposures.

Detection of DNA of Chlamydophila psittaci in subjects with psoriasis: a casual or a causal link?

BACKGROUND: Recent evidence indicates that subclinical infection by Chlamydophila psittaci occurs in a significant percentage of patients with chronic inflammatory polyarthritis, including psoriatic arthritis. OBJECTIVE: To assess the prevalence of Chlamydiae infection in a large cohort of well-characterized patients with psoriasis. METHODS: The presence of a subclinical C. psittaci infection was investigated in 64 patients with psoriasis, including 12 patients with psoriatic arthritis. Two hundred and twenty-five healthy controls were also investigated. The presence of infection was assessed in peripheral blood mononuclear cells using several polymerase chain reaction protocols, targeting different regions of the bacterial genome. The DNA of other species (Chlamydophila pneumoniae and Chlamydia trachomatis) was also investigated. RESULTS: Chlamydophila psittaci infection was observed in a significantly higher percentage of patients with psoriasis (11/64, 17%) compared with healthy controls (1/225, 0.4%) (odds ratio 46.49, 95% confidence interval 5.87-368.03; P < 0.0001). No differences in age, sex or disease duration were noticed between positive and negative patients, but the majority of the positive patients were on immunomodulatory treatments. CONCLUSION: Chlamydophila psittaci may be an infectious trigger possibly involved in the pathogenesis of psoriasis.

HLA DR-DQ combination associated with the increased risk of developing human HCV positive non-Hodgkin's lymphoma is related to the type II mixed cryoglobulinemia.

This investigation was focused on the contribution of individual human leukocyte antigen (HLA)-DR and -DQ alleles to the human hepatitis C virus (HCV)(+) non-Hodgkin's lymphoma (NHL), with and without mixed cryoglobulinemia (MC), to study whether individual HLA class II alleles are expressed preferentially or equally in human HCV-specific NHL. For this purpose, peripheral blood mononuclear cells were obtained from two groups of patients with HCV(+) NHL and with or without MC (70 and 71 cases, respectively), and from 4575 blood donors. Eighty-three subjects with HCV infection only, and 118 patients with MC, only without lymphoma, were added as additional control groups. Individual HLA-DR and -DQ alleles were determined using high-resolution sequence-based typing and then data were collected by considering the HLA-DRB1 and DQB1 supertypes on the basis of common structural and functional features, proposed by in silico Bioinformatic studies. From the data, it is evidenced that the DR5-DQ3 HLA combination was strongly associated with the HCV (+) MC (+) NHL group of patients compared with bone marrow donor population (P

Predictive Value of CD8 Expression and FoxP3 Methylation in Nasopharyngeal Carcinoma Patients Treated with Chemoradiotherapy in a Non-endemic Area.

Undifferentiated Nasopharyngeal Carcinoma (UNPC) is associated with Epstein-Barr Virus (EBV) and characterized by an abundant immune infiltrate potentially influencing the prognosis. Thus, we retrospectively assessed the significance of immunosuppression in the UNPC microenvironment as prognostic biomarker of treatment failure in a non-endemic area, and monitored the variation of systemic EBV-specific immunity before and after chemoradiotherapy (CRT). DNA and RNA were extracted from diagnostic biopsies obtained by tumor and adjacent mucosa from 63 consecutive EBV+ UNPC patients who underwent radical CRT. Among these patients 11 relapsed within 2 years. The expression of the EBV-derived UNPC-specific BARF1 gene and several immune-related genes was monitored through quantitative RT-PCR and methylation-specific PCR analyses. Peripheral T cell responses against EBV and BARF1 were measured in 14 patients (7 relapses) through IFN-γ ELISPOT assay. We found significantly higher expression levels of BARF1, CD8, IFN-γ, IDO, PD-L1, and PD-1 in UNPC samples compared to healthy tissues. CD8 expression was significantly reduced in both tumor and healthy tissues in UNPC patients who relapsed within two years. We observed a hypomethylated FOXP3 intron 1 exclusively in relapsed UNPC patients. Finally, we noticed a significant decrease in EBV- and BARF1-specific T-cells after CRT only in relapsing patients. Our data suggest that a high level of immunosuppression (low CD8, hypomethylated FoxP3) in UNPC microenvironment may predict treatment failure and may allow an early identification of patients who could benefit from the addition of immune modulating strategies to improve first line CRT.

HLA-A11 epitope loss isolates of Epstein-Barr virus from a highly A11+ population.

Cytotoxic T lymphocytes (CTLs) control viral infections by recognizing viral peptides presented by major histocompatibility complex (MHC) class I molecules. Human leukocyte antigen (HLA)-A11-restricted CTLs that recognize peptide residues 416 to 424 of the Epstein-Barr virus (EBV) nuclear antigen-4 frequently dominate EBV-induced responses in A11+ Caucasian donors. This epitope is conserved in type A EBV strains from Caucasians and central African populations, where A11 is relatively infrequent. However, strains from highly A11+ populations in New Guinea carry a lysine-to-threonine mutation at residue 424 that abrogates CTL recognition and binding of the peptide to nascent A11 molecules. The results suggest that evolution of a widespread and genetically stable virus such as EBV is influenced by pressure from MHC-restricted CTL responses.

Ocular adnexal MALT lymphoma: an intriguing model for antigen-driven lymphomagenesis and microbial-targeted therapy.

Non-Hodgkin's lymphomas constitute one half of malignancies arising in the orbit and the ocular adnexae. Mucosa-associated lymphoid tissue (MALT)-type lymphoma is the most common histological category in this anatomic region. The incidence of ocular adnexal lymphoma of mucosa-associated lymphoid tissue-type (OAML) is increasing and recent studies offered new relevant insights in molecular, pathogenetic and therapeutic issues on these neoplasms. A pathogenetic model of antigen-driven lymphoproliferation similar to that reported for Helicobacter pylori-related gastric MALT lymphomas has been hypothesized for OAML. This notion is supported by the association between OAML and Chlamydophila psittaci infection, an association that is of likely pathogenetic relevance and may influence both the biological behavior and the therapeutic management of these neoplasms. However, this association displays evident geographical variability indicating that other etiopathogenic agents could be involved. These recent acquisitions coupled with the occurrence of chromosomal translocations and other genetic alterations, as well as additional risk factors like autoimmune disorders have contributed to render OAML an exciting challenge for a broad group of physicians and scientists. OAML is an indolent and rarely lethal malignancy that, in selected patients, can be managed with observation alone. Lymphomatous lesions are frequently responsible for symptoms affecting patient's quality of life, requiring, therefore, immediate treatment. Several therapeutic strategies are available, often associated with relevant side-effects. However, the therapeutic choice in OAML is not supported by consolidated evidence due to the lack of prospective trials. In this review, we analyze the most relevant biological, molecular, pathological and clinical features of OAML and propose some therapeutic guidelines for patients affected by this malignancy.

Exploiting a new strategy to induce immunogenic cell death to improve dendritic cell-based vaccines for lymphoma immunotherapy.

Although promising, the clinical benefit provided by dendritic cell (DC)-based vaccines is still limited and the choice of the optimal antigen formulation is still an unresolved issue. We have developed a new DC-based vaccination protocol for aggressive and/or refractory lymphomas which combines the unique features of interferon-conditioned DC (IFN-DC) with highly immunogenic tumor cell lysates (TCL) obtained from lymphoma cells undergoing immunogenic cell death. We show that treatment of mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) cell lines with 9-cis-retinoic acid and IFNα (RA/IFNα) induces early membrane exposure of Calreticulin, HSP70 and 90 together with CD47 down-regulation and enhanced HMGB1 secretion. Consistently, RA/IFNα-treated apoptotic cells and -TCLs were more efficiently phagocytosed by DCs compared to controls. Notably, cytotoxic T cells (CTLs) generated with autologous DCs pulsed with RA/IFNα-TCLs more efficiently recognized and specifically lysed MCL or DLBCL cells or targets loaded with several HLA-A*0201 cyclin D1 or HLA-B*0801 survivin epitopes. These cultures also showed an expansion of Th1 and Th17 cells and an increased Th17/Treg ratio. Moreover, DCs loaded with RA/IFNα-TCLs showed enhanced functional maturation and activation. NOD/SCID mice reconstituted with human peripheral blood lymphocytes and vaccinated with autologous RA/IFNα-TCL loaded-IFN-DCs showed lymphoma-specific T-cell responses and a significant decrease in tumor growth with respect to mice treated with IFN-DC unpulsed or loaded with untreated TCLs. This study demonstrates the feasibility and efficacy of the use of RA/IFNα to generate a highly immunogenic TCL as a suitable tumor antigen formulation for the development of effective anticancer DC-based vaccines.

Identification and characterization of an Epstein-Barr virus-specific T-cell response in the pathologic tissue of a patient with Hodgkin's disease.

Several lines of evidence indicate that an impairment of EBV-specific immune responses may contribute to the pathogenesis of Hodgkin's disease (HD). At present, however, it is not clear whether a defective immunity to EBV is a characteristic restricted to EBV-associated HD cases or a more generalized phenomenon, part of the inherent immune deficiency of HD patients. In this study, we have addressed this issue by analyzing EBV-specific responses in infiltrating T lymphocytes (TILs) from one HD biopsy, where the virus was confined to a small proportion of apparently normal lymphocytes. TIL cultures were established using low amounts of recombinant interleukin 2 and in the absence of specific stimulation, conditions that preferentially induce the proliferation of in vivo activated T cells. An EBV-specific cytotoxic component was revealed by the capacity of these TILs to lyse autologous EBV-positive lymphoblastoid cell lines (LCLs) obtained by spontaneous transformation from the lesion but not HLA-mismatched LCLs and autologous phytohemagglutinin blasts. This cytotoxic activity closely resembled that of EBV-specific memory T cells, which may be reactivated from the blood lymphocytes of healthy donors by in vitro stimulation with autologous LCLs. The use of a panel of appropriately HLA-matched B95.8-transformed LCLs as targets in standard 51Cr release assays revealed EBV-specific cytotoxic responses to be restricted mainly through the A11 and B44 HLA alleles with a minor HLA-A26-restricted component. Using autologous fibroblasts infected with recombinant vaccinia viruses expressing the EBV latent antigens, the TIL culture was shown to recognize latent membrane protein 2 and, to a lesser extent, EBV-encoded nuclear antigen 6. In addition, a strong proliferative response was induced by coculture of TILs with autologous but not with allogeneic LCLs or autologous phytohemagglutinin blasts. Six CD4-positive, EBV-specific T-cell clones were isolated by limiting dilution. The study of cytokine mRNA expression, carried out by reverse transcriptase-assisted PCR, revealed that three of these T-cell clones expressed a Th0 phenotype, whereas 1 had a Th2 phenotype. These findings are consistent with the presence in this HD lesion of an ongoing immune response against EBV-carrying cells and suggest that the complex immune deficiency that characterizes HD patients probably does not include a generalized, constitutional defect of EBV-specific T-cell responses.

Retinoic acid-mediated growth arrest of EBV-immortalized B lymphocytes is associated with multiple changes in G1 regulatory proteins: p27Kip1 up-regulation is a relevant early event.

EBV-immortalized lymphoblastoid B cell lines (LCLs) are a suitable in vitro model for the study of EBV-related lymphoproliferative disorders of immunosuppressed patients. We have previously shown that 9-cis-, 13-cis- and all-trans-retinoic acid (RA) powerfully inhibit LCL proliferation at concentrations corresponding to therapeutically achievable plasma levels (10(-6) M). Herein we show that RA-induced LCL accumulation in the G0/G1 phases correlated with the loss of the catalytic activity of all three G1-associated CDKs (CDK2, CDK4 and CDK6) and with increased levels of underphosphorylated pRb and, in some LCLs, p130. LCLs arrested in G0/G1 by RA also showed a significant decrease in the protein levels of cyclins D2, D3 and A, together with a reduction in the amount of cyclin D associated with CDK4 and CDK6, probably accounting for the inhibition of the relative kinase activity. In addition, RA-treated LCLs showed a marked up-regulation of the CDK inhibitor (CKI) p27Kip-1 at the protein but not mRNA level, which correlated with a progressive increase of p27Kip-1 in CDK2 complexes (more than 2.5-fold) and with a reduction in the active phosphorylated form of CDK2. p27Kip-1 may also contribute to the inhibition of CDK4 kinase activity, as the amount of CDK4-associated p27Kip-1 was increased by 50% after RA exposure. p27Kip-1 up-regulation stably persisted for more than one week after RA withdrawal concomitantly with the maintenance of the proliferative block. Moreover, neutralization of TGFbeta did not affect the growth inhibitory activity of RA, suggesting that LCL growth arrest induced by these retinoids is probably not mediated by a pathway directly involving TGFbeta. Overall, these results demonstrate that RA treatment of EBV-immortalized B lymphocytes is associated with multiple effects on G1 regulatory proteins, including p27Kip1 up-regulation, decreased levels of cyclins D2, D3 and A, and inhibition of CDK2, CDK4 and CDK6 activity, which ultimately result in reduced pRb phosphorylation and G0/G1 growth arrest.

N-myc activation by proviral insertion in MCF 247-induced murine T-cell lymphomas.

N-myc proto-oncogene rearrangement was found in three out of six AKR murine T-cell lymphomas induced by the highly oncogenic MCF 247 MuLV. Molecular analyses showed that structural modification of the proto-oncogene in all three lymphomas was in the consequence of MCF 247 proviral integration within the gene III exon. All integrated proviruses have the same transcriptional orientation as the N-myc gene. As a consequence of proviral insertion, the N-myc gene becomes transcriptionally active, producing an abnormal mRNA. These findings suggest a possible causative role of such an integrative event in murine T-cell lymphomagenesis.

High frequency of p53 gene alterations associated with protein overexpression in human squamous cell carcinoma of the larynx.

A series of 58 primary human squamous cell carcinomas of the larynx (LSCCs) was examined for the expression of the p53 tumor-suppressor gene by a combined immunohistochemical and molecular approach. About 60% of the cases displayed nuclear p53 overexpression as revealed by immunostaining with PAb1801, PAb122 and PAb240 monoclonal antibodies. This phenomenon was associated with the presence of structural and/or transcriptional alterations of the p53 gene. Our results provide evidence that p53 abnormalities constitute the most frequent genetic alteration identified so far in LSCC and indicate that the abnormal accumulation of the protein correlates with the presence of p53-mutated versions. These findings, taken together with the peculiar biochemical properties of p53, support the hypothesis of a possible pathogenetic relationship between smoke carcinogen exposure and p53 inactivation in the development of this tumor type.

Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors.

PURPOSE: To describe virologic, clinicopathologic, and therapeutic features of a large series of Italian patients with Hodgkin's disease (HD) and human immunodeficiency virus (HIV) infection. PATIENTS AND METHODS: From November 1986 to March 1994, 114 cases were observed. The relationship between Epstein-Barr virus (EBV) and HD was determined by an in situ hybridization technique, immunostaining for EBV-encoded latent membrane protein-1 (LMP-1) expression, and Southern blotting. Twenty-six patients were included in a prospective study evaluating the combination of chemotherapy (CT) with zidovudine. RESULTS: Combined approach on EBV study revealed that 14 (78%) of 18 patients were EBV-associated. An almost equivalent distribution of EBV subtypes was observed in EBV-carrying cases, indicating that in the HIV setting, type 2 EBV also may be pathogenetically involved in HD development. In comparing these 114 patients with our single-institutional series of 104 HIV-negative patients with HD, we observed at presentation a younger median age (29 v 38 years); a prevalence of males (90% v 56%); and a higher percentage of stage IV disease (52% v 15%), presence of B symptoms (77% v 35%), and extranodal disease (63% v 29%). The complete remission (CR) rate (58%) and median survival (13 months) of patients treated prospectively were similar to that of patients treated with standard CT regimens. The statistically significant favorable prognostic factors for survival being the following: achievement of CR, CD4+ count greater than 250/microL, and no prior diagnosis of AIDS at onset of HD. CONCLUSION: Our virologic findings indicate that HIV-related HD is more closely associated with EBV than HD in the general population. The peculiar clinicopathologic findings, the role of some prognostic factors, and the possibility of cure of HIV-related HD have been demonstrated.

Adhesion molecule expression does not influence the leukemic behavior of murine T-cell lymphomas.

Recirculation and homing properties of normal lymphocytes are controlled by interactions with high endothelial venules (HEVs), specialized vessels which mediate the extravasation into lymphoid tissues. The present study was aimed at elucidating whether lymphoma-derived leukemic cell spreading and peripheral lymph node invasion ability are mediated by the recognition mechanisms which physiologically regulate normal lymphocyte trafficking. For this purpose, we tested the HEV-binding ability and the expression of the lymphocyte homing receptor (LHR) for peripheral lymph nodes as well as Pgp-1/CD44, LFA-1 and ICAM-1 adhesion molecules by the highly leukemic cell line NQ22 in comparison with a series of non-leukemic murine T-lymphoma cell lines. Our results indicate that the hematogenous spreading as well as peripheral node invasion of lymphoma-derived leukemic cells may occur independently of LHR expression. In addition, our findings seem to rule out that gross quantitative modifications in LFA-1 or ICAM-1 antigen expression are associated with differential dissemination abilities of transformed lymphoid cells.

Molecular profile of Epstein-Barr virus infection in HHV-8-positive primary effusion lymphoma.

Primary effusion lymphoma (PEL) selectively involves the serous body cavities, occurs predominantly in immunodeficient patients and is infected consistently by human herpesvirus type-8. PEL is also frequently infected by Epstein-Barr virus (EBV). The precise pathogenetic role of EBV coinfection in PEL is not fully understood. The lymphoma fails to express the EBV transforming proteins EBNA-2 and LMP-1, whereas it expresses EBNA-1 (latency I phenotype). Some studies have hypothesized that other EBV-positive lymphomas expressing the latency I phenotype may associate with specific molecular variants of EBNA-1, although this issue has not been addressed in PEL. On this basis, this study is aimed at a detailed molecular characterization of EBV in PEL. Fifteen EBV positive PEL (12 AIDS-related, one post-transplant, two arising in immunocompetent hosts) were subjected to molecular characterization of the viral genes EBNA-1 and LMP-1, as well as definition of EBV type-1/type-2. The EBNA-1 gene displayed a high degree of heterogeneity in different cases of PEL, with seven distinct recognizable variants and subvariants. A wild-type LMP-1 gene was detected in 10/15 cases, whereas in 5/15 cases the LMP-1 gene harbored a deletion spanning codons 346-355. EBV type-1 occurred in 11/15 PEL whereas EBV type-2 occurred in 4/15 cases. Despite a high degree of genetic variability of the virus in different PEL cases, each single PEL harbored only one EBV variant, consistent with monoclonality of infection and suggesting that infection preceded clonal expansion. Overall, our results indicate that: (1) individual PEL cases consistently harbor a single EBV strain; (2) EBNA-1 displays a high degree of heterogeneity in different PEL cases; (3) no specific EBV genotype preferentially associates with PEL.

Cross talk between EBV and telomerase: the role of TERT and NOTCH2 in the switch of latent/lytic cycle of the virus.

Epstein-Barr virus (EBV)-associated malignancies, as well as lymphoblastoid cell lines (LCLs), obtained in vitro by EBV infection of B cells, express latent viral proteins and maintain their ability to grow indefinitely through inappropriate activation of telomere-specific reverse transcriptase (TERT), the catalytic component of telomerase. Our previous studies demonstrated that high levels of TERT expression in LCLs prevent the activation of EBV lytic cycle, which is instead triggered by TERT silencing. As lytic infection promotes the death of EBV-positive tumor cells, understanding the mechanism(s) by which TERT affects the latent/lytic status of EBV may be important for setting new therapeutic strategies. BATF, a transcription factor activated by NOTCH2, the major NOTCH family member in B cells, negatively affects the expression of BZLF1, the master regulator of viral lytic cycle. We therefore analyzed the interplay between TERT, NOTCH and BATF in LCLs and found that high levels of endogenous TERT are associated with high NOTCH2 and BATF expression levels. In addition, ectopic expression of TERT in LCLs with low levels of endogenous telomerase was associated with upregulation of NOTCH2 and BATF at both mRNA and protein levels. By contrast, infection of LCLs with retroviral vectors expressing functional NOTCH2 did not alter TERT transcript levels. Luciferase reporter assays, demonstrated that TERT significantly activated NOTCH2 promoter in a dose-dependent manner. We also found that NF-κB pathway is involved in TERT-induced NOTCH2 activation. Lastly, pharmacologic inhibition of NOTCH signaling triggers the EBV lytic cycle, leading to the death of EBV-infected cells. Overall, these results indicate that TERT contributes to preserve EBV latency in B cells mainly through the NOTCH2/BAFT pathway, and suggest that NOTCH2 inhibition may represent an appealing therapeutic strategy against EBV-associated malignancies.

Pathogenetic and histogenetic features of HIV-associated Hodgkin's disease.

Compared with the cases in the general population, Hodgkin's disease (HD) arising in the HIV setting shows distinctive features in terms of epidemiology, aetiopathogenesis, histopathology and clinical behaviour. Although HD does not represent an AIDS-defining condition, recent evidence consistently indicates that HIV-infected individuals have a significantly increased risk of developing HD. HIV-related HD is characterised by the preponderance of aggressive histological subtypes, advanced stage at presentation, and highly malignant clinical course. Moreover, unlike HD in the general population, the large majority of HIV-related HD cases are pathogenetically linked to Epstein-Barr virus (EBV), with rates of EBV positivity ranging from 80 to 100%. Hodgkin and Reed-Sternberg cells of these cases invariably show a strong expression of the EBV-encoded latent membrane protein-1 (LMP-1), which functions as a constitutively activated tumour necrosis factor (TNF) receptor-like molecule. Usurpation of physiologically relevant pathways by LMP-1 may lead to the simultaneous or sequential activation of signalling pathways involved in the promotion of cell activation, growth, and survival, contributing thus to most of the features of HIV-related HD.

Hepatitis C virus-related hepatocellular carcinoma and B-cell lymphoma patients show a different profile of major histocompatibility complex class II alleles.

Comparison of human leukocyte antigen (HLA) frequencies in patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) and in patients with HCV-associated non-Hodgkin's lymphoma (NHL) has not been addressed previously. To this aim, we investigated the distribution of HLA class II alleles in two selected groups of HCV-infected patients. Group 1 included 50 patients with HCV-associated NHL; group 2 included 29 patients with HCV-associated HCC. A control group included 144 hospitalized patients without NHL or HCC and who were negative for HCV, hepatitis B virus, and human immunodeficiency virus antibodies. Polymerase chain reaction sequence DRB1 and DQB1 specific-primer methods were used. DRB1*1101/DQB1*0301 haplotype, which mainly favors the spontaneous clearance of HCV infection, was lower in HCC subjects than in controls, whereas HLA-DRB1*1104/DQB1*0301, was higher in NHL patients. These findings suggest different pathogenic pathways in HCC and in NHL development. In patients with HCV-associated HCC, a major protective role of DQB1*0301 allele, rather than DRB1*11, was found, probably because of a better HLA class II-associated virus clearance. By contrast, the same allele as HLA-DRB1*04 showed an increase in HCV-associated NHL. These data suggest that NHL and HCC development may be associated to a different response with respect to chronic HLA class II-restricted antigen presentation (perhaps a switch toward CD4+Th2 response in NHL?) or, alternatively, that these alleles could be in linkage disequilibrium to unrelated gene(s), or are in synergy with other immunomodulatory genes that may confer increased risk for NHL.

A coordinated proto-oncogene expression characterizes MCF 247 murine leukemia virus-induced T-cell lymphomas irrespectively of proviral insertion affecting myc loci.

Proto-oncogene transcriptional activation was analyzed in a group of MCF 247 MuLv-induced T-cell lymphomas to identify transformation-specific gene activations and determine whether the proviral insertion near a myc gene could promote a peculiar mechanism of transformation through a differential proto-oncogene expression pattern. Of the six lymphomas analyzed, three showed the MCF 247 provirus integrated within the N-myc locus, one carried the provirus integrated near c-myc, whereas for the remaining two, no evidence of proviral integrations in any of the known myc loci was obtained. Independently of the integrative events, the pattern of proto-oncogene expression was almost identical in all six lymphomas. These findings seem to rule out the existence of a peculiar pathway of transformation associated with the proviral insertion near a myc locus. Moreover, the transcription pattern observed was qualitatively identical to that displayed by normal thymocytes; only quantitative differences in c- or N-myc, c-myb and Ha-ras were observed. These results suggest that the T-cell proto-oncogene activation program is not qualitatively affected by the transforming event(s).