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Query: UNIPROT:P06889 (Mol)
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DP-1 is a G1 cell cycle-related protein that forms heterodimers with E2F, a family of transcriptional factors regulating the expression of genes important for G1 to S progression. Although the exact role of DP-1 is not well understood, it has been shown to stabilize DNA binding of E2F proteins. By immunohistochemistry, the authors examined the expression of DP-1 in lymphoid tissues, including 8 cases of reactive follicular hyperplasia and 69 cases of B-cell non-Hodgkin lymphoma. The expression of the cell cycle-related proteins E2F-1 and Ki-67 was also assessed. Scoring was based on the proportion of labeled nuclei (1-10%, 11-25%, 26-50%, and > 50%). In reactive follicular hyperplasia, staining for DP-1, E2F-1, and Ki-67 was largely confined to the germinal centers. All 25 cases of follicular lymphoma, regardless of grade, had a high proportion (> 50%) of DP-1-positive cells but a lower proportion of cells marking for E2F-1 and Ki-67 (P < 0.001). The diffuse large B-cell lymphomas (n = 24) had high DP-1 and Ki-67 scores but low E2F-1 scores (P < 0.001). Small lymphocytic (n = 10), marginal zone (n = 3), and mantle cell lymphomas (n = 5) contained relatively low proportions of cells labeled for all three markers. Precursor B-cell lymphoblastic lymphoma (n = 2) displayed high proportions of cells positive for DP-1, Ki-67, and E2F-1 (> 50% in both cases). Except in follicular center cell lesions, DP-1 expression generally correlated with that of Ki-67. However, the expression of DP-1 was discordant with that of E2F-1 in benign and malignant follicular center cells, suggesting that DP-1 may have functions other than facilitating E2F-1-dependent gene regulation and cell cycle progression in these neoplasms.
Appl Immunohistochem Mol Morphol 2002 Dec
PMID:Immunohistochemical expression of the transcription factor DP-1 and its heterodimeric partner E2F-1 in non-Hodgkin lymphoma. 1260

We have recently shown that MUC1, mapped to the chromosomal band 1q21, is rearranged or amplified in 15% of B-cell lymphomas and that rearrangement led to over-expression of MUC-1 mucin in a case of diffuse large B-cell lymphoma (DLBCL). To determine the incidence of MUC-1 mucin expression and its clinical significance in B-cell lymphomas, we investigated a panel of 113 cases by immunohistochemistry (IHC). MUC-1 mucin expression was detected in the majority of cases (92.9%), with moderate to high levels noted in 50.4% of all histologic subsets comprising DLBCL (82 cases), follicular lymphoma (FL) (15 cases), FL with transformation to DLBCL (4 cases), and other B-cell lymphomas (12 cases). No statistically significant correlation was found between MUC-1 mucin expression and MUC1 genomic status (amplification/rearrangement) evaluated by Southern blot analysis, and 1q21 abnormality by karyotypic analysis. For all cases, MUC-1 mucin expression correlated with a previous history of lymphoma (p=0.003).
Appl Immunohistochem Mol Morphol 2003 Mar
PMID:MUC-1 mucin protein expression in B-cell lymphomas. 1261 Mar 53

Non-Hodgkin's lymphomas are a heterogeneous group of malignancies of the lymphoid system. The exact etiology for most lymphomas has not been determined, but both viral and bacterial infections have been shown to be important etiologic factors. The WHO classification of hematopoietic and lymphoid tumours classifies lymphomas into B-cell and T-cell neoplasms. B-cell lymphomas account for more than 85% of all lymphomas. The Ann Arbor staging classification has been adopted by the AJCC and UICC as a standard for classifying extent of anatomic disease. The two most common histologic disease entities are follicular lymphomas and diffuse large B-cell lymphomas. The management of follicular lymphomas is used as a paradigm for the management of all indolent lymphomas. Radiation therapy is used for stage I and II disease, while alkylating agent chemotherapy, immunotherapy and radioimmunotherapy are most frequently used in stage III and IV disease that requires treatment. Most patients with follicular lymphoma enjoy prolonged survival, but at present there is no evidence that those with stage III and IV follicular lymphoma can be cured. Diffuse large B-cell lymphomas serve as a paradigm for treating aggressive lymphomas. Stage I and II diffuse large cell lymphomas are generally treated with combined modality therapy with doxorubicin-based chemotherapy followed by involved field radiation therapy, while those with stage III and IV disease are treated with chemotherapy alone. Patients who fail initial management are treated with further chemotherapy. High-dose chemotherapy with stem cell rescue has been shown to be particularly effective as salvage treatment for diffuse large cell lymphomas. The management of a heterogeneous group of primary extranodal lymphomas in general follows the above treatment principles, with additional treatment being required for those with a high risk of CNS failures, or involvement of contralateral paired organs. The management of MALT lymphomas, especially gastric MALT lymphoma, deserves special attention because of the high response rate to Helicobacter pylori eradication therapy.
Eur J Nucl Med Mol Imaging 2003 Jun
PMID:Therapy of non-Hodgkin's lymphoma. 1269 88

We herein present a technical strategy to optimize DNA isolation from paraffin-embedded tissue (PET). This includes the choice of adequate buffers for proteinase K digestion and multiplex PCR amplifications for assessing the appropriateness of DNA extracts for subsequent PCR assays for detecting clonality. We found that the association of proteinase K digestion in nonionic buffer and subsequent extract dilutions accounted for 79% of successful amplifications. A final efficiency of 88% was achieved by additional organic extractions and/or re-extractions. Comparisons were carried out with control DNA extracts from fresh samples to assess the efficiency of each clonality assay. Immunoglobulin CDRIII rearranged region amplification was more efficient for pregerminal center B-cell lymphomas in contrast to CDRII rearrangement detection, which was more effective for germinal and postgerminal lymphomas. T-cell clonality detection by TCRgamma PCR was less efficient in PET samples than in fresh tissues showing that DNA integrity is more critical for TCR than for IGH amplification. Two inconclusive cases without phenotypic markers and two other atypical lymphoproliferations masked by reactive T cells were diagnosed as plasmablastic lymphomas and as monoclonal B-proliferations, respectively, due to IGH rearrangements.
Diagn Mol Pathol 2003 Jun
PMID:Laboratory strategies for efficient handling of paraffin-embedded tissues for molecular detection of clonality in non-hodgkin lymphomas. 1276 12

Many indolent lymphomas are destined for eventual transformation to aggressive B-cell lymphomas, an event with significant impact on therapy and outcome. Specific morphologic patterns of transformation are described for common subtypes of low-grade B-cell lymphoma. The discussion highlights immunophenotypic, molecular, and genetic characteristics of lymphoma transformation.
Appl Immunohistochem Mol Morphol 2003 Sep
PMID:Transformation to aggressive B-cell lymphoma: morphology, immunophenotype, and molecular characteristics. 1296 45

The Epstein-Barr virus (EBV) is a human herpesvirus that is usually carried lifelong as an asymptomatic infection. EBV is the causative agent of infectious mononucleosis and has been linked to the development of several malignant tumours, including B-cell neoplasms such as Burkitt's lymphoma and Hodgkin's disease, certain forms of T-cell lymphoma, and some epithelial tumours, such as undifferentiated nasopharyngeal carcinoma and a proportion of gastric cancers. All these tumours are characterised by the presence of multiple extrachromosomal copies of the circular viral genome in the tumour cells and the expression of EBV-encoded latent genes, which appear to contribute to the malignant phenotype. An increasing understanding of the function of EBV latent genes and of the nature of the immune response to the virus is providing exciting new possibilities for the treatment of EBV-associated malignancies. For example, adoptive transfer of virus-specific cytotoxic T lymphocytes has already been of value in the treatment of EBV-positive B-cell lymphomas arising in post-transplant patients, and this approach is currently being investigated in other EBV-associated tumours. In addition, gene therapy offers the opportunity to deliver agents that might directly interfere with the function of specific EBV genes. This review summarises the role of EBV in malignancy. In particular, it focuses on the latent proteins as a basis for understanding how EBV might contribute to the process of transformation. Strategies to target EBV in tumours, potentially providing alternative therapeutic approaches, are also discussed.
Expert Rev Mol Med 2001 Nov 15
PMID:Epstein-Barr virus infection: basis of malignancy and potential for therapy. 1458 52

SWAP-70 is a recently discovered member of the Dbl (diffuse B-cell lymphoma) family of signal transduction molecules that is abundantly expressed in B cells. SWAP-70 mediates lipid second-messenger signals to the cytoskeletal-organizing GTPase Rac, functioning as a guanine-nucleotide exchange factor. SWAP-70 is strongly expressed in germinal center B cells, with low-level expression in resting B-cells. Expression of SWAP-70 in neoplastic B cells has not been described. We report the immunohistochemical expression of SWAP-70 in 86 B-cell neoplasms. SWAP-70 was strongly expressed in 59 of the 86 cases: 2 of 10 (20%) precursor B-cell lymphoblastic leukemias, 2 of 2 (100%) precursor B-cell lymphoblastic lymphomas, 2 of 4 (50%) mantle cell lymphomas, 7 of 9 (78%) Burkitt lymphomas, 9 of 9 (100%) diffuse large B-cell lymphomas, 8 of 8 (100%) follicular lymphomas, 6 of 6 (100%) nodular lymphocyte predominant Hodgkin lymphomas, 0 of 8 (0%) classic Hodgkin lymphomas, 12 of 13 (92%) chronic lymphocytic leukemias, 3 of 3 (100%) nodal marginal zone lymphomas, 5 of 5 (100%) extranodal marginal zone lymphomas, 1 of 2 (50%) splenic marginal zone lymphomas, 2 of 3 (66%) hairy cell leukemias, and 0 of 4 (0%) plasma cell neoplasms. All 4 T-cell lymphomas were nonreactive for SWAP-70: 0 of 3 peripheral T-cell lymphomas and 0 of 1 anaplastic large cell lymphoma. These results suggest that a spectrum of neoplastic B cells maintains activation of this signal transduction pathway. This is the first report of the expression of a Dbl family molecule in human lymphoma and leukemia tissues.
Appl Immunohistochem Mol Morphol 2004 Mar
PMID:Expression of the diffuse B-cell lymphoma family molecule SWAP-70 in human B-cell neoplasms: immunohistochemical study of 86 cases. 1516 14

Progression of follicular lymphomas (FLs) is often accompanied by a spectrum of histologic changes and an aggressive clinical course. Although molecular alterations have been implicated in this event, the underlying factors are largely unknown. We studied the expression of selected tumor suppressor genes (P53 and retinoblastoma [RB]), oncogenes (MYC and BCL2), and a transferrin-receptor related protein (Trump) in sequential biopsies in 16 patients. Eleven patients progressed from grade I or II FL to aggressive B-cell lymphomas with diffuse morphology, whereas 5 patients presented with diffuse aggressive lymphomas and recurred with indolent lymphomas. Immunoreactivity for P53 correlated with higher histologic grade in lymphomas progressing from indolent to aggressive; however, only 1 patient who presented with aggressive lymphoma demonstrated a P53 gene mutation. Neither P53 immunoreactivity nor genotypic alterations correlated with presentation with an aggressive histology and relapse with FL. Growth fraction, as assessed by Ki-67 staining, and Trump expression correlated with histologic grade. Immunoreactivity for RB, BCL2, and MYC was seldom associated with progression. Eight of 9 cases tested exhibited identical immunoglobulin heavy and light chain rearrangements or identical BCL2 gene rearrangements in the sequential lymphomas. We conclude that P53 and Trump protein expression and proliferation activity correlate with histologic grade, but not with recurrence or progression of FL. Our results further indicate that progression of FL to diffuse aggressive lymphomas and presentation of an aggressive B-cell lymphoma followed by FL are clonally related.
Appl Immunohistochem Mol Morphol 2004 Jun
PMID:Immunophenotypic and genotypic characterization of progression in follicular lymphomas. 1535 33

The International Network of Cancer Treatment and Research (INCTR) recently organized a workshop on non-Hodgkin lymphomas (NHLs) in selected developing countries with the purpose of examining existing information relating to the pathology and management of these neoplasms, and identifying potential areas for research. This report provides a summary of the information presented and is focused primarily on the pathology of NHLs in children and adults. In most countries, the WHO classification of lymphomas was used and most participating centers included immunohistochemistry using a wide array of lymphoid antibodies as part of routine diagnosis. Some of the series had been reviewed by an external panel of experts. B-cell lymphomas accounted for 82-88% of all NHLs. The proportions of chronic lymphatic leukemia (4-6%), mantle cell lymphoma (MCL, 3-5%), and plasmacytoma (2-4%) were similar in the series presented. However, there was a significant variation in the proportion of follicular lymphoma (FL), which accounted for 15% and 11% in India and Kuwait, but less than 5% in Pakistan and Egypt. All of these frequencies are significantly lower than those reported in Western series. Diffuse large B-cell lymphoma accounted for about 35% of cases in India but for more 50% in other countries, but this difference was not accounted for by an increased incidence in a single lymphoma subtype in India, but rather an apparent paucity of several subtypes (such as mantle cell and marginal zone lymphomas (MZL)) in other series. There were relatively high frequencies of Burkitt lymphoma in Egypt (7%) and precursor T-cell lymphoblastic lymphoma in India (6-7%). Peripheral T-cell lymphomas (PTCLs) (not otherwise specified and angioimmunoblastic subtypes) accounted for 3-5% of NHLs, and extranodal lymphoma of T/NK cell type was rare (<1%). These differences in the relative proportions of NHL subtypes among developing countries and between developing countries and the rest of the world presumably arise from differences in environmental and genetic factors that influence lymphomagenesis and strongly suggest that more research in developing countries would provide valuable insights into the pathogenesis of lymphoid neoplasms.
Blood Cells Mol Dis
PMID:Report of an International Network of Cancer Treatment and Research workshop on non-Hodgkin's lymphoma in developing countries. 1552 53

Overexpression of Bcl-2/Bcl-X(L) protein has been observed in more than 80% of B-cell lymphomas. Diffuse large cell lymphoma (DLCL) is the most common subtype of non-Hodgkin's lymphoma. (-)-Gossypol, a natural product isolated from cottonseeds, was discovered as a potent small-molecule inhibitor of Bcl-2 and Bcl-X(L) proteins, with a Ki value in the nanomole per liter range for both. In vitro, (-)-gossypol showed significant growth inhibition effect against WSU-DLCL2 lymphoma cell line and fresh cells obtained from a lymphoma patient with no effect on normal peripheral blood lymphocytes. As expected (-)-gossypol induced complete cytochrome c release from mitochondria, increased caspases-3 and -9 activity, and caused apoptotic death without affecting protein levels of Bcl-2, Bcl-X(L), Bax, and Bak. The addition of cyclophosphamide-Adriamycin-vincristine-prednisolone (CHOP) regimen to lymphoma cells preexposed to (-)-gossypol enhanced killing significantly. The maximum tolerated dose of (-)-gossypol in severe combined immunodeficient (SCID) mice was 40 mg/kg for three i.v. injections when given alone and 20 mg/kg x 3 when given in combination with CHOP. Using WSU-DLCL2-SCID mouse xenograft model, the tumor growth inhibition, the tumor growth delay, and the log10 kill of mice treated with (-)-gossypol + CHOP were better than CHOP or (-)-gossypol alone. We conclude that adding Bcl-2/Bcl-X(L) small-molecule inhibitor to standard chemotherapy may prove an effective strategy in lymphoma therapy.
Mol Cancer Ther 2005 Jan
PMID:Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma. 1565 49


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