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1.
Leukemia ; 30(3): 594-604, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26530011

ABSTRACT

PRDM1/Blimp1, a master regulator of B-cell terminal differentiation, has been identified as a tumor suppressor gene in aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL). It has been shown in DLBCL and Hodgkin lymphoma that PRDM1 is downregulated by cellular microRNAs. In this study, we identify the Epstein-Barr virus (EBV) microRNA (miRNA), EBV-miR-BHRF1-2, as a viral miRNA regulator of PRDM1. EBV-miR-BHRF1-2 repressed luciferase reporter activity by specific interaction with the seed region within the PRDM1 3' untranslated region. EBV-miR-BHRF1-2 inhibition upregulated PRDM1 protein expression in lymphoblastoid cell lines (LCL), supporting a role of miR-BHRF1-2 in PRDM1 downregulation in vivo. Discordance of PRDM1 messenger RNA and protein expressions is associated with high EBV-miR-BHRF1-2 levels in LCLs and primary post-transplant EBV-positive DLBCL. Enforced expression of PRDM1-induced apoptosis and cell cycle arrest in LCL cells. Inhibition of EBV-miR-BHRF1-2 negatively regulates cell cycle and decreases expression of SCARNA20, a small nucleolar RNA that is also downregulated by PRDM1 overexpression. The interaction between EBV-miR-BHRF1-2 and PRDM1 may be one of the mechanisms by which EBV-miR-BHRF1-2 promotes EBV lymphomagenesis. Our results support the potential of EBV-miR-BHRF1-2 as a therapeutic target in EBV-associated lymphoma.


Subject(s)
Carcinogenesis/genetics , Epstein-Barr Virus Infections/genetics , Gene Expression Regulation, Neoplastic , Lymphoma, Large B-Cell, Diffuse/genetics , MicroRNAs/genetics , Repressor Proteins/genetics , Viral Proteins/genetics , 3' Untranslated Regions , Base Sequence , Binding Sites , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Cycle Checkpoints , Cell Line, Tumor , Epstein-Barr Virus Infections/metabolism , Epstein-Barr Virus Infections/pathology , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/pathogenicity , Host-Pathogen Interactions , Humans , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , MicroRNAs/metabolism , Molecular Sequence Data , Paraffin Embedding , Positive Regulatory Domain I-Binding Factor 1 , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , RNA, Small Nucleolar/genetics , RNA, Small Nucleolar/metabolism , Repressor Proteins/metabolism , Signal Transduction , Tissue Fixation , Viral Proteins/antagonists & inhibitors , Viral Proteins/metabolism
2.
Blood Cancer J ; 4: e261, 2014 Nov 07.
Article in English | MEDLINE | ID: mdl-25382611

ABSTRACT

PRDM1/Blimp-1 is a tumor suppressor gene in the activated B-cell subtype of diffuse large B-cell lymphomas. Its inactivation contributes to pathogenesis in this setting by impairing terminal B-cell differentiation induced by constitutive nuclear factor-κB activation. The role of PRDM1 in Burkitt lymphoma (BL) lymphomagenesis is not known. Here we identified hypermethylation of the promoter region and exon 1 of PRDM1 in all six Epstein-Barr virus (EBV)-positive BL cell lines and 12 of 23 (52%) primary EBV-positive BL or BL-related cases examined, but in none of the EBV-negative BL cell lines or primary tumors that we assessed, implying a tumor suppressor role for PRDM1 specifically in EBV-associated BL. A direct induction of PRDM1 hypermethylation by EBV is unlikely, as PRDM1 hypermethylation was not observed in EBV-immortalized B lymphoblastoid cell lines. Treatment of EBV-positive BL cells with 5' azacytidine resulted in PRDM1 induction associated with PRDM1 demethylation, consistent with transcriptional silencing of PRDM1 as a result of DNA methylation. Overexpression of PRDM1 in EBV-positive BL cell lines resulted in cell cycle arrest. Our results expand the spectrum of lymphoid malignancies in which PRDM1 may have a tumor suppressor role and identify an epigenetic event that likely contributes to the pathogenesis of BL.


Subject(s)
Burkitt Lymphoma/metabolism , DNA Methylation , Herpesvirus 4, Human , Repressor Proteins/metabolism , Tumor Suppressor Proteins/metabolism , Burkitt Lymphoma/genetics , Burkitt Lymphoma/pathology , Burkitt Lymphoma/virology , Cell Line, Tumor , Female , Humans , Male , Positive Regulatory Domain I-Binding Factor 1 , Repressor Proteins/genetics , Tumor Suppressor Proteins/genetics
4.
Mod Pathol ; 24(1): 108-16, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20852592

ABSTRACT

Splenic hamartoma is a rare tumor-like lesion composed of structurally disorganized red pulp elements. It has been hypothesized that two other splenic lesions, cord capillary hemangioma and myoid angioendothelioma, may fall within the spectrum of splenic hamartoma, simply representing morphological variants. In this study, we compared the vascular and stromal composition of cord capillary hemangioma and myoid angioendothelioma with those of classical hamartoma. In addition, we assessed the clonal vs polyclonal nature of the lesions in nine female cases by performing clonality analysis for X-chromosome inactivation at the human androgen receptor locus (HUMARA) on laser-assisted microdissected samples. In 15 of 17 cases, increased reticulin and/or collagen content was observed. The classical hamartoma cases showed a vasculature predominantly composed of CD8+ CD31+ CD34- splenic sinuses, whereas cases of cord capillary hemangioma and myoid angioendothelioma contained many CD8- CD31+ CD34+ cord capillaries, but very little CD8+ vasculature. All cases lacked expression of D2-40 and Epstein Barr virus-encoded RNA. All cases showed a proliferation index of ≤5% by Ki-67. Cases of classical hamartoma lacked significant perisinusoidal expression of collagen IV and low-affinity nerve growth factor receptor. Both markers were variably expressed in the other lesions. Increased CD163-positive histiocytes were found in four cases (three cord capillary hemangiomas and one myoid angioendothelioma). HUMARA analysis was informative in all nine tested cases, of which three cases showed a non-random X-chromosome inactivation pattern, indicating clonality. All three clonal cases were cord capillary hemangiomas. Our study has shown that in spite of considerable morphologic heterogeneity and overlapping features, classical hamartoma and cord capillary hemangioma and myoid angioendothelioma are different in terms of their vascular and stromal composition. Clonality analysis supports a true neoplastic origin for the cord capillary hemangioma. A larger study using additional immunohistochemical and molecular studies is necessary to further evaluate the biological significance of the current findings.


Subject(s)
Chromosomes, Human, X , Hamartoma/genetics , Hemangioma, Capillary/genetics , Splenic Neoplasms/genetics , X Chromosome Inactivation/genetics , Adolescent , Adult , Aged , Child , Clone Cells , Diagnosis, Differential , Female , Hamartoma/pathology , Hemangioendothelioma/genetics , Hemangioendothelioma/pathology , Hemangioma, Capillary/pathology , Humans , Male , Middle Aged , Splenic Neoplasms/pathology , Young Adult
5.
Histopathology ; 53(5): 513-24, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18983461

ABSTRACT

AIMS: Kaposi sarcoma herpesvirus (KSHV) is aetiologically related to Kaposi sarcoma, classical and extracavitary primary effusion lymphoma (PEL; EC-PEL) and multicentric Castleman disease (MCD), entities preferentially occurring in HIV-infected individuals. Characterization of HIV-associated PELs/EC-PELs suggests that the KSHV-infected malignant cells originate from a pre-terminal stage of B-cell differentiation. However, only limited phenotypic studies have been performed on HIV+ MCD, including for PR domain containing 1 with zinc finger domain/B lymphocyte-induced maturation protein 1 (PRDM1/BLIMP1), a key regulator of terminal B-cell differentiation. The aim was to characterize KSHV-infected cells in 17 cases of HIV+ MCD. METHODS AND RESULTS: Double immunohistochemistry and immunohistochemistry-in situ hybridization were used to characterize the KSHV-infected cells in MCD; the results were compared with the phenotypic profiles of 39 PELs/EC-PELs and seven PEL cell lines. Whereas the immunophenotype of KSHV-infected cells in MCD and malignant KSHV+ PEL cells was similar (PAX5, Bcl-6-; PRDM1/BLIMP1, IRF4/MUM1+; Ki67+), the MCD KSHV-infected cells differed, as they expressed OCT2, cytoplasmic lambda immunoglobulin; variably expressed CD27; lacked CD138; and were Epstein-Barr virus negative. CONCLUSIONS: Although both PEL and MCD originate from KSHV-infected pre-terminally differentiated B cells, these findings, with previously reported genetic studies, indicate HIV+ MCD may arise from extrafollicular B cells, whereas PELs may originate from cells that have traversed the germinal centre.


Subject(s)
B-Lymphocytes/virology , Castleman Disease/virology , HIV Infections/complications , Herpesviridae Infections/virology , Herpesvirus 8, Human , Lymphoma, Primary Effusion/virology , Adult , B-Lymphocytes/metabolism , Castleman Disease/immunology , Castleman Disease/metabolism , Cell Differentiation , Female , Herpesvirus 8, Human/immunology , Herpesvirus 8, Human/metabolism , Humans , Immunohistochemistry , Immunophenotyping , In Situ Hybridization , Lymphoma, Primary Effusion/immunology , Male , Middle Aged
6.
Leukemia ; 22(9): 1755-66, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18596745

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although some patients can be cured by current therapies, novel agents are needed to further improve outcomes. We hypothesized that Src tyrosine kinase inhibition by dasatinib may have antilymphoma effects. Here, we demonstrate that dasatinib inhibits cell growth through G(1)-S blockage in five of seven DLBCL cell lines at clinically achievable concentrations. Compared to resting B cells, DLBCL has increased tyrosine phosphorylation activities. As expected, dasatinib inhibits phosphorylation of several Src family kinase members. However, this inhibition occurs in all cell lines regardless of their proliferative response to the drug. In contrast, the activity of two downstream signaling molecules, Syk and phospholipase Cgamma2 (PLCgamma2), are well correlated with cell line sensitivity to dasatinib, suggesting that these molecules are crucial in mediating the proliferation of activated lymphoma cells. Furthermore, dasatinib inhibits B-cell receptor signaling in primary lymphoma cells. Together, our findings not only show dasatinib as a potentially useful therapy for DLBCL but also provide insights into the pathogenesis of the lymphoma. The results further suggest the possibility of using Syk and PLCgamma2 as biomarkers to predict dasatinib therapeutic response in prospective clinical trials.


Subject(s)
Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Lymphoma, Large B-Cell, Diffuse/drug therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Thiazoles/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Dasatinib , Humans , Interphase/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Phospholipase C gamma/metabolism , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Receptors, Antigen, B-Cell/metabolism , Syk Kinase , src-Family Kinases/antagonists & inhibitors
7.
Ann Oncol ; 19(7): 1327-1330, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18349031

ABSTRACT

BACKGROUND: Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3-4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion. METHODS: We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival. RESULTS: We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63-98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS. CONCLUSION: Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.


Subject(s)
Biomarkers, Tumor/analysis , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/pathology , Lymphoma, Mantle-Cell/therapy , Stem Cell Transplantation , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Clinical Trials as Topic , Cohort Studies , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Databases, Factual , Dexamethasone/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Lymphoma, Mantle-Cell/diagnosis , Lymphoma, Mantle-Cell/mortality , Lymphoma, Mantle-Cell/radiotherapy , Male , Middle Aged , Neoplasm Staging , Prednisone/administration & dosage , Radiotherapy , Regression Analysis , Retrospective Studies , Rituximab , Survival Analysis , Time Factors , Transplantation, Autologous , Treatment Outcome , Vincristine/administration & dosage
8.
Histopathology ; 41(1): 1-29, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12121233

ABSTRACT

Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.


Subject(s)
Biomarkers, Tumor , Dendritic Cells/immunology , Histiocytes/immunology , Histiocytic Disorders, Malignant/classification , Lymphoma/classification , Adult , Aged , Biomarkers, Tumor/immunology , Dendritic Cells/classification , Female , Histiocytes/classification , Histiocytes/ultrastructure , Histiocytic Disorders, Malignant/diagnosis , Histiocytic Disorders, Malignant/immunology , Humans , Immunohistochemistry , Immunophenotyping , Lymphoma/diagnosis , Lymphoma/immunology , Lymphoma/ultrastructure , Male , Microscopy, Electron , Middle Aged
9.
Virology ; 287(1): 62-70, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11504542

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) encodes a G protein-coupled receptor (vGPCR) in open reading frame (ORF) 74, which is homologous to human chemokine receptors. KSHV vGPCR is constitutively active and induces VEGF-mediated angiogenesis. Previous studies have shown that ORF 74 is transcribed as part of a bicistronic message containing ORF K14 upstream of ORF 74, with an early lytic pattern of expression. We have now extended these studies by analyzing three different KSHV-positive primary effusion lymphoma (PEL) cell lines and three PEL clinical samples. In addition, we have identified another less abundant monocistronic transcript containing only ORF 74. Both transcripts were identified at low but similar levels in two PEL clinical samples. We evaluated the degree of sequence and functional conservation of ORF74 in three additional PELs and two KS clinical specimens, demonstrating complete identity at the amino acid level among all isolates. While it is expressed as an early lytic transcript in PEL cell lines, in primary clinical PEL samples transcription of KSHV vGPCR can be readily detected.


Subject(s)
Herpesvirus 8, Human/genetics , Lymphoma/virology , Receptors, Chemokine/biosynthesis , Amino Acid Sequence , Base Sequence , Castleman Disease/genetics , Castleman Disease/virology , Humans , Lymphoma/genetics , Molecular Sequence Data , Open Reading Frames , Receptors, Chemokine/genetics , Sarcoma, Kaposi/genetics , Sarcoma, Kaposi/virology , Structure-Activity Relationship , Tumor Cells, Cultured
11.
J Mol Diagn ; 3(1): 32-8, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11227070

ABSTRACT

Since its discovery in 1994, KSHV (also called human herpesvirus-8 or HHV8) has been implicated in a variety of disorders. Although the association of KSHV with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease has been well established, its presence in some other diseases, such as multiple myeloma, remains controversial. Because most KSHV studies are based on polymerase chain reaction (PCR) analysis, the conflicting data may be attributable to variations in the methods, primer sets, and target sequences selected. To establish an efficient and reliable PCR approach for KSHV detection we designed eight sets of primers to six regions (ORFK1, ORFK2, ORFK9, ORK26, ORF72, and ORF74) of the KSHV genome using appropriate database and software. The detection sensitivity of these primers was carefully assessed and their reliability was strictly validated in a series of positive (15 KS and PEL samples) and negative (16 lymphoid tissues) controls. We found that primer sets to the ORFK9 region showed the highest sensitivity, whereas primer sets to ORFK1 and ORF74 showed the lowest sensitivity. Primer sets to ORFK9, ORF26 and ORF72 regions detected all of the positive cases, whereas other primer sets showed varying detection rates or nonspecific bands. All 16 negative controls were negative with all primer sets. However, six of 16 negative controls became positive when we used nested PCR targeting ORF26. Therefore, multiple target KSHV sequences increase the detection efficiency, while nested PCR protocols are likely to introduce false positivity. Using ORFK9, ORF26 and ORF72 primer sets, we screened bone marrow biopsies from 18 cases of multiple myeloma, and failed to detect any KSHV sequences. This finding supports the conclusion that KSHV is not associated with multiple myeloma. Indeed, our results further confirm that although KSHV is universally present in Kaposi's sarcoma and primary effusion lymphoma, it is not ubiquitious.


Subject(s)
Herpesvirus 8, Human/isolation & purification , Multiple Myeloma/virology , Polymerase Chain Reaction/methods , Sarcoma, Kaposi/virology , Archives , DNA Primers , Herpesvirus 8, Human/genetics , Humans , Lymphoma/virology , Sensitivity and Specificity , Tissue Banks
13.
Blood ; 97(1): 270-6, 2001 Jan 01.
Article in English | MEDLINE | ID: mdl-11133771

ABSTRACT

The organization and expression of the BCL-6 gene in normal and neoplastic thymic T cells has not been fully determined. We examined 8 precursor T-cell lymphoblastic lymphomas (T-LBLs) and found significant BCL-6 expression in 4 cases. Three of the BCL-6(+) cases expressed a common thymocyte phenotype (CD4(+), CD8(+)), and one expressed a precursor thymocyte phenotype (CD4(-), CD8(-)). In 6 cases evaluated, including those expressing BCL-6, molecular analyses demonstrated a germline configuration of the BCL-6 gene and a wild-type BCL-6 gene first exon-intron boundary region. We also evaluated 12 normal prenatal and postnatal thymuses for BCL-6 protein. BCL-6 was expressed by most cortical thymocytes and by scattered medullary thymocytes. BCL-6(+) cortical and medullary thymocytes also expressed CD2, CD3, CD4, CD5, CD7, or CD8. We further analyzed the pattern of BCL-2 and BCL-X(L) expression and their coexpression with BCL-6 in normal thymus and T-LBL and compared it to that of follicle centers of reactive lymph nodes and follicular lymphoma. BCL-6(+) cortical thymocytes coexpressed BCL-X(L) but not BCL-2. All 4 BCL-6(+) T-LBLs and 4 BCL-6(-) T-LBLs coexpressed BCL-2 and BCL-X(L). Conceivably, T-LBLs may arise through clonal expansion of cortical thymocytes normally expressing the BCL-6 protein. The pattern of BCL-6, BCL-2, and BCL-X(L) expression in cortical thymocytes is highly reminiscent of germinal centers, and the abnormal coexpression of BCL-2, BCL-X(L), and BCL-6 in T-LBL is analogous to coexpression in follicle center cell lymphomas, suggesting that coexpression of these anti-apoptotic genes may contribute to the pathogenesis of T-LBL.


Subject(s)
DNA-Binding Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Thymus Gland/embryology , Transcription Factors/metabolism , Adolescent , Adult , Apoptosis/drug effects , Child , Child, Preschool , Female , Fetus/chemistry , Fetus/cytology , Humans , Immunophenotyping , Infant , Infant, Newborn , Lymphoma, Follicular/etiology , Lymphoma, Follicular/metabolism , Lymphoma, T-Cell/etiology , Lymphoma, T-Cell/metabolism , Lymphoma, T-Cell/pathology , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-bcl-6 , Thymus Gland/chemistry , Thymus Gland/pathology , bcl-X Protein
14.
Cancer ; 89(2): 445-52, 2000 Jul 15.
Article in English | MEDLINE | ID: mdl-10918178

ABSTRACT

BACKGROUND: Studies have shown telomerase activity to be present in some B-cell non-Hodgkin lymphomas (B-NHLs). However, no large studies have assayed telomerase activity in a systematic and quantitative manner. Furthermore, the relation between telomerase and proliferation suggested by in vitro studies has not been adequately tested in B-NHLs in vivo. This information is necessary to understand the relation between proliferation and telomerase and to predict the efficacy of antitelomerase drugs currently in development. METHODS: Eighteen benign biopsies and 111 B-NHLs of varying types were classified according to the revised European-American classification of lymphoid neoplasms (REAL classification) and assayed for telomerase activity and proliferation index (PI). RESULTS: All B-NHLs contained telomerase activity except for low grade marginal zone B-cell lymphomas (MZBCLs) (96 of 111, 86%) (chi(2) 95.90, P < 0.001). Telomerase activity correlated with PI (r = 0.7536, r(2) = 0.5678, t = 10.51, P < 0.001) and showed a threshold whereby telomerase activity was not present below a PI of 9.2% (t = 4.875, P < 0.001). CONCLUSIONS: The level of telomerase activity fell within characteristic ranges and generally correlated with the clinical aggressiveness of each B-NHL category. Low grade MZBCLs of extranodal, nodal, and splenic types were unique among the categories of B-NHL in lacking or containing very little telomerase activity. The association between telomerase activity and PI is evidence that telomerase is controlled in vivo along with the cell cycle and is not constitutively active in B-NHL. These data provide evidence that antitelomerase drugs may be efficacious in most types of B-NHL.


Subject(s)
Lymphoma, B-Cell/enzymology , Telomerase/metabolism , Cell Division/physiology , Humans , Lymphoma, B-Cell/classification , Lymphoma, B-Cell/pathology
15.
Hum Immunol ; 61(12): 1242-53, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11163079

ABSTRACT

To investigate the role of somatic Ig hypermutation in the evolution of AIDS-associated B cell lymphomas, we analyzed the Ig V(D)J and c-myc genes expressed by neoplastic B cells in two extranodal sites, testis and orbit, and clonally related cells in the bone marrow. Testis and orbit B cells expressed differentially mutated but collinear V(H)DJ(H), V kappa J kappa and c-myc gene sequences. Shared mutations accounted for 10.2%, 8.4%, and 4.3% of the overall V(H)DJ(H), V kappa J kappa, and c-myc gene sequences. Tumor-site specific V(H)DJ(H), V kappa J kappa, and c-myc mutations were comparable in frequency, and a single point-mutation gave rise to an EcoRI site in the testis c-myc DNA. Both shared and tumor site-specific V(H)DJ(H), V kappa J kappa, and c-myc mutations displayed predominance of transitions over transversions. The "neoplastic" V(H)DJ(H) sequence was expressed by about 10(-5) cells in the bone marrow, and contained two of the three orbital, but none of the testicular V(H)DJ(H) mutations. The nature and distribution of the Ig V(D)J mutations found in the kappa chain suggested a selection by antigen in testis and orbit. Our data suggest that, in AIDS-associated B cell lymphomas, the Ig hypermutation machinery targets V(H)DJ(H), V kappa J kappa, and c-myc genes with comparable efficiency and modalities.


Subject(s)
Antibody Diversity/genetics , B-Lymphocytes/immunology , Burkitt Lymphoma/immunology , Genes, myc/immunology , Immunoglobulin Joining Region/genetics , Immunoglobulin Variable Region/genetics , Lymphoma, AIDS-Related/immunology , Point Mutation , Adult , Amino Acid Sequence , B-Lymphocytes/pathology , Base Sequence , Binomial Distribution , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , Burkitt Lymphoma/genetics , Burkitt Lymphoma/pathology , Cell Differentiation/genetics , Cell Differentiation/immunology , Clone Cells/immunology , Clone Cells/pathology , Gene Frequency/immunology , Gene Rearrangement, B-Lymphocyte, Heavy Chain , Gene Rearrangement, B-Lymphocyte, Light Chain , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin kappa-Chains/genetics , Lymphoma, AIDS-Related/genetics , Lymphoma, AIDS-Related/pathology , Male , Molecular Sequence Data , Orbital Neoplasms/genetics , Orbital Neoplasms/immunology , Proto-Oncogene Mas , Testicular Neoplasms/genetics , Testicular Neoplasms/immunology
16.
Hum Pathol ; 30(8): 981-4, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10452513

ABSTRACT

Primary effusion lymphoma (PEL) is a rare and distinctive type of B-cell non-Hodgkin's lymphoma (NHL) that occurs primarily, although not exclusively, in patients with AIDS. It usually develops as a lymphomatous effusion in the absence of a tumor mass, characteristically contains the Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8), usually also contains the Epstein-Barr virus (EBV), displays a characteristic cytomorphology bridging immunoblastic and anaplastic large cell lymphoma, often expresses an indeterminate immunophenotype, and a B-cell genotype. Thus far, PEL has been limited almost entirely to the pleural, peritoneal, and pericardial cavities. We describe a NHL occurring in a gay man with AIDS that is typical of PEL in that it arose in a body cavity or space without an associated tumor mass, displays the cytomorphology typical of PEL, is a clonal B-cell neoplasm, and contains KSHV as well as EBV. This case is singularly distinctive in that it is the first case of PEL reported to arise in the subarachnoid space. This unique case further supports the strong association between KSHV and malignant lymphoma arising in body cavities and growing as an effusion.


Subject(s)
Herpesvirus 8, Human/isolation & purification , Lymphoma, AIDS-Related/diagnosis , Lymphoma, B-Cell/diagnosis , Meningeal Neoplasms/diagnosis , Subarachnoid Space , Adult , Biomarkers, Tumor/metabolism , Herpesvirus 4, Human/isolation & purification , Humans , Immunohistochemistry , In Situ Hybridization , Lymphoma, AIDS-Related/metabolism , Lymphoma, AIDS-Related/pathology , Lymphoma, AIDS-Related/virology , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/virology , Male , Meningeal Neoplasms/metabolism , Meningeal Neoplasms/pathology , Meningeal Neoplasms/virology , Polymerase Chain Reaction
17.
Hum Pathol ; 30(8): 988-92, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10452515

ABSTRACT

Although follicle center cell lymphoma and mantle cell lymphoma are both B cell non-Hodgkin's lymphomas (NHL), they are regarded as separate entities with distinct clinical, morphological, immunophenotypic and molecular characteristics. To our knowledge, the coexistence of these 2 lymphomas in the same patient has never been reported. We describe a 70-year-old woman with a long-standing history of follicle center cell lymphoma, cytological grade I, who subsequently developed a composite lymphoma consisting of well-demarcated foci of persistent follicle center cell lymphoma surrounded by mantle cell lymphoma. This morphological interpretation was supported by the presence of both bcl-1 and bcl-2 gene rearrangements, which are molecular genetic hallmarks of mantle cell lymphoma and follicle center cell lymphoma, respectively. Polymerase chain reaction (PCR) analysis for rearranged immunoglobulin heavy chain (IgH) genes showed a dominant band identical in size in microdissected tumor cells of the follicle center cell and mantle cell lymphomas. Cloning and sequence analysis of the PCR products revealed a common clone-specific IgH gene rearrangement in these 2 lymphomas. These findings suggest that this composite lymphoma represents the unusual evolution of a malignant B-cell clone that resulted in the development of 2 morphologically distinct but clonally related B-cell NHLs. These findings also show the importance of integrating morphological, immunophenotypic, and molecular data to enhance our understanding of the complex pathogenic interrelationships in lymphomagenesis.


Subject(s)
Lymphoma, Follicular/pathology , Lymphoma, Non-Hodgkin/pathology , Aged , Antigens, CD/metabolism , Blotting, Southern , Female , Humans , Immunophenotyping , Lymphoma, Follicular/genetics , Lymphoma, Follicular/metabolism , Lymphoma, Non-Hodgkin/genetics , Lymphoma, Non-Hodgkin/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Translocation, Genetic
18.
Semin Cancer Biol ; 9(3): 165-74, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10343068

ABSTRACT

The Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), has been found to be present in a limited subset of lymphoproliferative disorders. Among these are the primary effusion lymphomas, formerly designated body cavity-based lymphomas, a rare type of malignant lymphoma which possesses an unusual set of clinical and biologic features, suggesting that they represent a distinct disease entity. This virus is also present in a large proportion of cases of multicentric Castleman's disease, particularly those associated with HIV-infection. In addition, KSHV has been implicated in the pathogenesis of multiple myeloma, where it has been identified in bone marrow adherent cells but not in the neoplastic myeloma plasma cell population. However, the latter finding remains controversial. The discovery of KSHV in a subset of malignant lymphomas has allowed the development of lymphoma cell lines which now serve as biological reagents for propagating the virus, as a substrate for serologic assays, and as a model system for pathobiologic studies. This review discusses the features of KSHV-associated lymphoproliferative disorders and the evidence supporting its role in the pathogenesis of these diseases.


Subject(s)
Castleman Disease/virology , Herpesvirus 8, Human/isolation & purification , Lymphoma/virology , Multiple Myeloma/virology , Herpesvirus 8, Human/genetics , Humans , Lymphoma/etiology , Tumor Cells, Cultured
19.
Eur J Immunol ; 29(4): 1253-64, 1999 04.
Article in English | MEDLINE | ID: mdl-10229093

ABSTRACT

An outcome of low-grade B cell non-Hodgkins's lymphomas is the transformation to high-grade diffuse large B cell lymphomas (DLBL). To investigate the mechanisms of clonal evolution in the transformation to DLBL, we performed longitudinal molecular analyses of immunoglobulin (Ig), V(H)DJ(H) gene sequences expressed in cases of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL) that transformed to DLBL. Among the neoplastic CLL and SLL cells and their respective high-grade transformants, there was no evidence for a clonotypic shift or acquired mutations in the expressed Ig V(H)DJ(H) gene segments, as further confirmed by a specific and sensitive PCR-single strand polymorphism analysis. In contrast, among the FL cells there was a high degree of intraclonal diversification with highly divergent V(H)DJ(H) gene sequences. Despite this intraclonal heterogeneity, the related DLBL expressed a collinear but unique V(H)DJ(H) gene sequence. The intraclonal genealogical tree for the FL case demonstrated that the DLBL emerged in association with unique V(H)DJ(H) gene mutational events. Among the intraclonal FL and related DLBL transformants, the nature and distribution of the Ig V(H)DJ(H) gene mutations were consistent with antigenic selection. Thus, clonal evolution in the transformation from low- to high-grade B cell lymphoma may involve distinct pathways which vary according to the cellular origin and the type of the progenitor B cell tumor.


Subject(s)
B-Lymphocytes/physiology , Lymphoma, B-Cell/immunology , Lymphoma, Non-Hodgkin/etiology , Lymphoma, Non-Hodgkin/immunology , Amino Acid Sequence , Base Sequence , Gene Rearrangement , Genes, Immunoglobulin , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Joining Region/genetics , Immunoglobulin Variable Region/genetics , Molecular Sequence Data , Mutation
20.
Mod Pathol ; 12(2): 200-17, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10071343

ABSTRACT

The incidence of lymphoproliferative disease is significantly higher in individuals who have congenital, acquired, or iatrogenically induced immunodeficiency. The immunodeficiency-associated lymphoproliferative disorders are clinically and pathologically heterogeneous, are of variable clonal composition, and vary according to the immunodeficiency syndrome. Nonetheless, they share several features, including frequent origination in or involvement of extranodal sites, diffuse aggressive histology, B-cell lineage derivation, association with the Epstein-Barr virus (EBV), and, often, rapid clinical progression. Reactive and atypical lymphoid hyperplasias and malignant lymphomas occur in association with congenital (primary) immunodeficiency. Post-transplantation lymphoproliferative disorders are often comprised of a polymorphic cell population, making it difficult to identify their benign or malignant nature by histopathologic criteria alone. Recent studies suggest that they are divisible into plasmacytic hyperplasias, polymorphic lymphoproliferative disorders, and malignant lymphomas. The plasmacytic hyperplasias are polyclonal and generally regress spontaneously following withdrawal of immunosuppression. The malignant lymphomas are monoclonal, possess a variety of genetic alterations, and generally progress despite aggressive therapy. The polymorphic lymphoproliferative disorders are also monoclonal but display variable clinical behavior, their progression apparently correlating with bcl-6 gene mutation. Non-Hodgkin's lymphoma (NHL) is the second most common AIDS-related neoplasm and an AIDS-defining illness. AIDS-related NHLs are divisible by anatomic site of origin into systemic (nodal/extra nodal), primary central nervous system, and body cavity-based (primary effusion) lymphomas; and by histopathology into Burkitt's and Burkitt's-like lymphoma, large cell lymphoma, and large cell immunoblastic (plasmacytoid) lymphoma More than 90% are monoclonal B-cell neoplasms. The primary effusion lymphomas contain the Kaposi's sarcoma-associated herpesvirus. Multiple molecular pathways appear to operate in AIDS lymphomagenesis and some may be preferentially associated with specific histopathologic categories or anatomic sites of origin. In conclusion, the immunodeficiency-associated lymphoproliferative disorders often represent a significant diagnostic problem requiring correlative analysis of the clinical behavior of the patient with the histopathology, immunophenotype, clonal composition, viral content, and genetic alterations of the lymphoproliferative disorder. They also represent an important biological model for studying the development and progression of lymphoid neoplasia


Subject(s)
Immunosuppression Therapy/adverse effects , Lymphoproliferative Disorders/immunology , Humans , Lymphoma, AIDS-Related/immunology , Lymphoma, AIDS-Related/pathology , Lymphoproliferative Disorders/classification , Lymphoproliferative Disorders/pathology
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