The V410I (G1228A) variant of the caspase-10 gene is a common polymorphism of the Danish population.
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Caspase 10↗
Biomedical subjects
E Ralfkiaer
Publications and source records attributed to E Ralfkiaer.
Apoptosis-related genes and proteins in Hodgkin's disease.
During recent years it has become increasingly evident that L&H cells in nodular lymphocytic predominance (LP) Hodgkin's disease (HD) and Hodgkin and Reed-Sternberg (H-RS) cells in approximately half the cases of classical HD originate from B-lymphocytes, and that H-RS cells in most of the remaining cases of classical HD express a null phenotype. The pathogenesis of HD is unknown. An association with Epstein-Barr virus (EBV) has been suggested and there are also indications that genes involved in programmed cell death (apoptosis) may be implicated. In this study, the expression of four apoptosis-related proteins (bcl-2, bcl-x, bax and p53) in 53 cases of HD was examined and the data were correlated with the genotype, the EBV status and the phenotype (B, T or null) of the neoplastic cells. The H-RS cells expressed a B-cell phenotype in 3/3 cases of nodular LP and in 19/ 50 (38%) cases of classical HD. The remaining cases showed a null-cell phenotype in 29/50 (58%) and a T-cell phenotype in 2/50 (4%). EBV was more often positive in B (14/19, 74%) than in null (7/29, 24%) type HD. The H-RS cells were bcl-2-positive in 19/53 (36%), bcl-x-positive in 17/53 (32%), bax-positive in 1/53, and p53-positive in 41/53 (77%) cases. No relationship was found between bcl-2 expression and EBV status, or between bcl-2 and bcl-x expression. A t(14;18) translocation was seen in 2 of 34 cases. P53 point mutations were not detected. Our findings indicate that nodular LP and classical HD originate from B-cells in a high proportion of cases. They also suggest a role for bcl-2, bcl-x and p53 in tumorigenesis. The pathogenesis is not known at this stage.
Animals↗
Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity.
Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of the Fas gene in 150 cases of non-Hodgkin's lymphoma. Overall, mutations were identified in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant-negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with somatic Fas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity.
Adult↗
Alterations of the MMAC1/PTEN gene in lymphoid malignancies.
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Chromosomes, Human, Pair 10↗
Co-expression of CD79a (JCB117) and CD3 by lymphoblastic lymphoma.
Acute lymphoblastic leukaemia/lymphoma is a malignant disorder derived from the clonal proliferation of lymphoid precursor cells. Whether the tumour cells are of B- or T-cell type is an important criterion for prognosis which has not been available previously to pathologists, due to the lack of a reliable early B-cell marker functioning on routinely processed material. This has changed with the production of monoclonal antibodies against the B-cell signalling molecule CD79a. CD79a is expressed on normal and neoplastic B cells from the early stages of B-cell maturation and has been considered to be B-cell-specific. Currently available antibodies against CD79a, in particular JCB117, allow the identification of B cells, and hence B lymphoblastic disease, in paraffin-embedded material. In this study, the expression of CD79a (JCB117) and CD3 has been investigated in 149 cases of T and 68 cases of B lymphoblastic leukaemia/lymphoma. For the first time, co-expression of CD79a (JCB117) and CD3 is reported in 10 per cent of cases of T lymphoblastic leukaemia/lymphoma. This finding raises questions about the co-expression of T- and B-cell markers in the development of lymphocytes, benign as well as malignant, and alerts pathologists to a potential problem in diagnosis.
Antigens, CD↗
Concurrent disruption of cell cycle associated genes in mantle cell lymphoma: a genotypic and phenotypic study of cyclin D1, p16, p15, p53 and pRb.
Mantle cell lymphomas (MCL) are morphologically and immunophenotypically distinctive lymphoid neoplasms characterised by overexpression of cyclin D1. Recent studies have suggested that co-operating aberrations of cell cycle associated genes may provide a growth advantage to a tumour. To address this issue further, we investigated five typical and three aggressive (blastoid) MCL for alterations in the cell cycle regulating genes p15, p16, CDK4, Rb and p53. In 3/3 aggressive cases with cyclin D1 overexpression we found aberration of at least one additional gene. One case showed diminished expression of the retinoblastoma protein (pRb); one case harboured deletion of both p15 and p16; and one case exhibited both deletion of p16 and point mutation of p53. However, we also identified two typical cases which in addition to cyclin D1 overexpression exhibited diminished pRb expression and p15 and p16 hypermethylation, respectively. Our findings confirm and extend other recent investigations and indicate that co-operating genetic alterations of cell cycle-associated genes may contribute to the pathogenesis of MCL.
Adult↗
T-cell receptor variable region genes in cutaneous T-cell lymphomas.
The genes encoding the T-cell receptor (TCR) variable beta (TCRBV) regions were studied in skin biopsy samples from 24 patients with cutaneous T-cell lymphomas (CTCL), i.e. mycosis fungoides (n = 7), Sézary syndrome (n = 4), lymphomatoid papulosis (n = 3) and large cell CTCL with (n = 3) or without (n = 7) CD30 expression. A panel of 24 primers specific for TCRBV families 1-24 was designed and applied to cDNA using a semiquantitative reverse transcriptase coupled polymerase chain reaction (PCR) method. Three patients showed restricted expression of a limited number (1-3) of TCRBV families. In the remaining patients, an average of 17 (range: 13-22) different families was expressed. All patients showed elevated (> 10%) expression of individual families significantly higher than that seen in normal blood lymphocytes, but no preferential usage of particular gene families was observed. Direct sequence analysis of more than 60 PCR products revealed clonal TCR transcripts in 18 patients. A single T-cell clone, constituting 9-100% (mean: 26%) of the TCRBV mRNA, was present in 12 patients; two T-cell clones, constituting 13-72% (mean: 21.5%) of the TCRBV mRNA, were present in five patients; and three T-cell clones, accounting for < 0.5-13% of the TCRBV mRNA, were present in one patient. In the remaining six patients, clonal TCR transcripts could not be identified. It is concluded that most CTCL contain both clonal and non-clonal (reactive) T cells, and that the latter cells are more numerous than anticipated. These cells may be engaged in tumour immune reactions, although prospective studies and/or serial investigations are needed to elucidate this issue fully.
Adult↗
Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats.
The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats. Here we have investigated how the development and progression of this leukaemia affect oxygenation, pH and proliferation of normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to identify hypoxic cells, and we applied bromodeoxyuridine (BrdUrd) to identify DNA replicating cells. The leukaemia progressed slowly until day 27 after which a rapid deterioration could be observed leading to severe changes over the following 5 d. In whole blood there was evidence of progressing metabolic acidosis. In bone marrow the fraction of leukaemic cells increased to > 90% and the pH dropped to about 6.5. The fraction of NITP+ cells increased to > 80% in bone marrow and to about 40% in blood. The fraction of BrdUrd+ cells was unchanged in blood, but decreased in bone marrow both for normal cells (from about 20% to 5%), and for leukaemic cells (from about 45% to 25%), evidently as a result of the severely changed microenvironment. In this study we have demonstrated in vivo the development of an acidic and hypoxic bone marrow hampering normal haemopoiesis during leukaemic growth. Our data support the notion of BNML as a valuable tool for studying leukaemogenesis.
Acute Disease↗
Primary gastrointestinal non-Hodgkin's lymphoma in adults: a population-based clinical and histopathologic study.
OBJECTIVES: To analyse the clinical course and the histopathology of primary gastrointestinal non-Hodgkin's lymphoma (GI-NHL) in adult patients and to investigate a possible impact of Helicobacter pylori. DESIGN/SETTING: Retrospective study of all adult patients in Copenhagen county diagnosed during a 6-year period with NHL. SUBJECTS: A total of 55 patients with GI-NHL diagnosed during the period from 1985 to the end of 1990. RESULTS: Twenty-eight patients had primary lymphoma in the stomach, 14 in the small intestine, 11 in the large intestine and two patients had multifocal involvement. The dominant presenting symptoms were abdominal pain, weight loss, diarrhoea, constipation and fatigue. Acute emergency problems such as severe haemorrhage or perforation at initial presentation were unusual. According to the revised European-American lymphoma (REAL) classification, diffuse large B-cell lymphoma was the most frequent histologic subtype comprising 53% of the cases. Helicobacter pylori infection was documented in 15 of 25 evaluable patients (60%) with gastric lymphomas and was not associated with any specific histological subtype. Endoscopic procedures and barium X-rays were the diagnostic approaches with highest sensitivity. In total, 30 patients (58%) achieved complete remission, 10 (19%) achieved partial remission, and 12 (23%) did not respond to treatment. The overall 5 year survival rate was 0.36 without statistically significant difference between the histological subtypes. Likewise the presence of Helicobacter pylori did not affect survival. CONCLUSION: Primary GI-NHL is a heterogeneous disease entity with considerable therapeutic controversies. No specific clinical or histological phenotype was associated with the presence of Helicobacter pylori.
Adult↗
EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer.
Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas that show considerable variation in histology, phenotype, and prognosis. Recently, the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group has reached consensus on a new classification for this group of diseases. The EORTC classification for primary cutaneous lymphomas is based on a combination of clinical, histologic, and immunophenotypic criteria, and thus contains well-defined disease entities rather than histologic subgroups. In addition, this new classification contains a number of provisional entities, which may display characteristic histologic features, but are not yet well defined clinically. These provisional entities account for less than 5% of all primary cutaneous lymphomas. In this report the basic principles of this new classification, as well as the characteristic features of the different disease entities, are described. In addition, survival data of 626 patients with primary cutaneous lymphomas derived from the registry of the Dutch Cutaneous Lymphoma Working Group, illustrating the clinical validity of this new classification, are presented.
Humans↗
A one-step DGGE scanning method for detection of mutations in the K-, N-, and H-ras oncogenes: mutations at codons 12, 13 and 61 are rare in B-cell non-Hodgkin's lymphoma.
Mutations in the N-, K-, and H-ras genes are key events in the process of carcinogenesis of many human cancers and may serve as important targets for therapeutic intervention. We developed a simple diagnostic method that in one step and within 5 hr determines the mutational status of any of the 3 ras genes in a given tumor sample. The method combines polymerase chain reaction (PCR) with denaturing gradient gel electrophoresis (DGGE) and allows simultaneous mutation scanning of 6 regions covering "hot-spot" codons 12, 13 and 61 of the 3 ras genes. The sensitivity of the assay was demonstrated by the analysis of control mutations, either naturally occurring or created by site-directed mutagenesis. We further demonstrate that unambiguous identification of ras mutations can be achieved by heteroduplex analysis in denaturing gradient gels, circumventing sequence analysis. We applied the method to establish the mutational status of all 3 ras genes in 123 samples of B-cell non-Hodgkin's lymphoma. Altogether, one diffuse large B-cell lymphoma and one B-cell chronic lymphocytic leukemia (B-CLL) harbored a mutation (G12S and G12A, respectively) in the K-ras gene, and one B-CLL harbored a mutation (Q61R) in the N-ras gene. We therefore conclude that ras mutations only contribute rarely, if at all, to carcinogenesis in B-cell non-Hodgkin's lymphoma.
Base Sequence↗
CD34+ megakaryoblastic leukaemic cells are CD38-, but CD61+ and glycophorin A+: improved criteria for diagnosis of AML-M7?
The aim of this flow cytometry study in acute megakaryoblastic leukaemia (AML-M7) was to describe the membrane phenotype of CD34+ progenitor subsets and compare these with the phenotypes expressed by other AML FAB types. Following conventional histopathological diagnosis mononuclear cells from bone marrow and blood were examined in seven patients with AML-M7 and compared with results from 26 sequential patients with AML-M0 to AML-M6. The CD34+ subsets in AML-M7 patients differed from that of patients with AML-M0 to AML-M6 as the CD34+ CD61+ and the CD34+ Glycophorin A+ subsets were median 31% and 20%, respectively, compared to 4% and 2% in the AML-M0 to AML-M6 (P = 0.0005). Only 1% of the CD34+ progenitors were CD34+ CD38+ in AML-M7 compared to 72% in other AML subtypes (P < 0.000). These findings suggest that the CD34+ cell compartment in AML-M7 consists of early lineage-specific progenitors. In conclusion, flow cytometry analysis of CD34+ subsets may improve the diagnostic safety in AML-M7 and consequently the prognostic significance of immunophenotyping in acute leukaemia.
Adult↗
An immunohistochemical study of TAL-1 protein expression in leukaemias and lymphomas with a novel monoclonal antibody, 2TL 242.
Fifty formalin fixed, paraffin-embedded cases of T-acute lymphoblastic leukaemia (T-ALL) from 12 bone marrow trephines and 38 lymph nodes were stained with a new monoclonal antibody, 2TL 242, raised against recombinant TAL1 protein. The antibody recognizes TAL-1 polypeptides of molecular weight 39 and 41 kD (full length). In addition, a variety of other leukaemias and lymphomas were also stained with 2TL 242. Twenty-four of the 50 cases of T-ALL showed nuclear positivity, ranging from 10 to 90 per cent of leukaemic cells. A positive staining reaction was nuclear and stippled in pattern. Nuclear staining was not seen in any other type of leukaemia or lymphoma. Five cases of follicular lymphoma showed diffuse cytoplasmic staining of variable intensity. Although some background staining is obtained with this antibody, positive nuclear staining is easily distinguishable. This monoclonal antibody has a potential role in primary diagnosis and in the detection of minimal residual disease in T-ALL.
Antibodies, Monoclonal↗
Differential expression of urokinase-type plasminogen activator, its receptor, and inhibitors in mouse skin after exposure to a tumor-promoting phorbol ester.
The cellular distribution of mRNAS for urokinase-type plasminogen activator (uPA), its specific receptor (uPAR), and its inhibitors (PAI-1 and -2) in mouse skin was analyzed by in situ hybridization after topical application of the tumor promoter phorbol 12-myristate 13-acetate. In the epidermis, strong signals for uPA and PAI-1 mRNA were detected 24 h after treatment in the basal and suprabasal epidermal keratinocytes in areas with pronounced hyperproliferation and increased terminal differentiation, and in some hair follicle keratinocytes. After 48 h, both uPAR and PAI-2 mRNAs were expressed in the epidermal layers from the suprabasal keratinocytes up to the differentiating cells beneath the cornified layer and in hair follicle keratinocytes. Induction of PAI-2 mRNA was detected in epidermis as early as 3 h after treatment and remained stable for up to 7 days. In the dermis, 5 h after application of phorbol 12-myristate 13-acetate to the skin, uPA mRNA was detected in fibroblast-like cells below and around the skin muscle, and PAI-1 mRNA was detected in stromal cells located above the skin muscle. After longer exposure to phorbol 12-myristate 13-acetate, the PAI-1 mRNA-expressing stromal cells were located more superficially, apparently moving toward the epidermal layer. After 9 h, most of the PAI-1 mRNA-positive cells were identified as endothelial cells. Up to 24 h after the application of phorbol 12-myristate 13-acetate, the intensity of the signal for both uPA and PAI-1 increased, followed by a gradual decrease for up to 7 days. These results show that in mouse skin treated with a tumor-promoting phorbol ester, the various components of the plasminogen activation system are expressed by both epithelial and stromal cell types, which in dermis and subcutis are located in different places, depending on the time of exposure to the phorbol ester. Our results suggest that urokinase-mediated extracellular proteolysis has diverse functional roles during the early steps of tumor promotion.
Animals↗
A novel antigen detected by the CBF.78 antibody further distinguishes anaplastic large cell lymphoma from Hodgkin's disease.
A novel antigen detected by the CBF.78 monoclonal antibody (MoAb) is strongly expressed on cortical thymocytes and weakly expressed on resting peripheral T lymphocytes. Expression of the antigen is increased on phytohemagglutinin (PHA)- and anti-CD3-activated T lymphocytes and on Epstein-Barr virus-transformed B lymphocytes. The CBF.78 immunoprecipitated a protein of 116 kD from resting and PHA-activated peripheral blood mononuclear cells. CBF.78 MoAb did not inhibit T-cell proliferation induced by anti-CD3 antibody. This MoAb was effective for immunostaining on paraffin sections after microwave-oven heating of tissue sections. Among malignant lymphomas, the antigen recognized by CBF.78 MoAb was found to be mainly expressed by T-cell lymphomas (49+ of 74), particularly those of high-grade malignancy (31+ of 36), whereas only occasional B-cell lymphomas (4+ of 107) expressed the antigen. A distinctive pattern of reactivity was shown by 108 cases of anaplastic large cell lymphomas. Strong positivity for CBF.78 antibody was observed in 86+ of 108 cases, irrespective of B, T, or null phenotype. This multicenter study suggests that CBF.78 MoAb could be of diagnostic value in differentiating Hodgkin's-like anaplastic large cell lymphomas from cases of Hodgkin's disease rich in neoplastic cells. Only a few cases of Hodgkin's disease (13+ of 126) showed rare Reed-Sternberg cells that stained, In these few cases, staining was weak to moderate and confined to cytoplasm. CBF.78 MoAb was nonreactive with all nonhematopoietic neoplasms examined (0+ of 48). Further studies should delineate the function of this new antigen and its clinical utility.
Animals↗
Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas.
Recombinant human gamma 2 chain of laminin-5 was expressed in Escherichia coli, and used to generate specific polyclonal antibodies which were used to study the distribution of the protein in human cancers. A total of 72 biopsies of human cancers were stained, including 23 cases of colon adenocarcinomas, 16 ductal breast carcinomas, 9 malignant melanomas, 14 squamous cell carcinomas of the skin and cervix, and 10 sarcomas. As a control for the specificity of the antibodies, we performed in situ hybridization on adjacent sections of a number of the cases, and in all of these cases the localization of the gamma 2 chain protein and mRNA was identical. We found gamma 2 chain immunoreactivity in cancer cells in all cases of colon adenocarcinomas and squamous cell carcinomas but not in any of the sarcomas, supporting the view that the laminin-5 protein is specific for cells of epithelial origin. Notably, in all of the cases of colon adenocarcinomas, the positive staining was invariably associated with budding cancer cells located at the tip of invading malignant epithelium, whereas the cancer cells deeper in the tumors were most often negative. The staining was cytoplasmic in all cases and only in one case did we see additional extracellular immunoreactivity, indicating that this laminin isoform in cancer tissue is not laid down in the extracellular matrix but probably exerts its function at the cell surface or in its immediate vicinity. Using in situ hybridization to analyze the coexpression of laminin-5 and components of the plasminogen activation system, we found that the histological distribution of laminin-5-positive budding cancer cells at the invasion front in colon adenocarcinomas was identical to that of the receptor for urokinase-type plasminogen activator. These findings suggest that laminin-5 is a marker of invading cancer cells in at least some human malignancies, and that it therefore might represent a valuable marker for the invasive potential of these cancers. The colocalization of laminin-5 and urokinase-type plasminogen activator receptor in a subset of cancer cells in colon cancer also suggests that a controlled up-regulation of a number of gene products is a characteristic of budding colon cancer cells, and that these gene products serve functions crucial for the invasive phenotype of these cancer cells.
Adenocarcinoma↗
CD79a: a novel marker for B-cell neoplasms in routinely processed tissue samples.
The CD79 molecule, comprising two polypeptide chains, mb-1 (CD79a) and B29 (CD79b), is physically associated in the B-cell membrane with immunoglobulin. It transmits a signal after antigen binding and may, therefore, be considered the B cell equivalent of CD3. It appears before the pre-B-cell stage, and the mb-1 (CD79a) chain can still be present at the plasma cell stage. In this report, we describe a new anti-CD79a monoclonal antibody, JCB117, which reacts with human B cells in paraffin embedded tissue sections, including decalcified bone marrow trephines. When tested on a total of 454 paraffin embedded tissue biopsies, gathered from a number of different institutions, it reacted with the great majority (97%) of B-cell neoplasms, covering the full range of B-cell maturation, including 10 of 20 cases of myeloma/plasmacytoma. It is of interest that the antibody labels precursor B-cell acute lymphoblastic leukemia samples, making it the most reliable B-cell marker detectable in paraffin-embedded specimens in this disorder. All neoplasms of T cell or nonlymphoid origin were negative, indicating that antibody JCB117 may be of value to diagnostic histopathologists for the identification of B-cell neoplasms of all maturation stages.
Antibodies, Monoclonal↗
SCL/Tal-1 expression in T-acute lymphoblastic leukemia: an immunohistochemical and genotypic study.
A comparative study of the immunohistochemical (Stem cell leukemia/T-cell acute leukemia [SCL/TAL-1] protein expression) and genotypic (deletions in the SCL/tal-1 gene) findings in T-acute lymphoblastic leukemia (T-ALL) is presented. Formalin-fixed tissue from 50 cases of T-ALL were stained with a novel monoclonal antibody, 2TL 242, which recognizes SCL/TAL-1 protein. Twenty-four cases showed nuclear immunolabeling of leukemic cells. Nuclear positivity was not evident in any other type of leukemia or lymphoma tested with the antibody. Genotypic analysis of 25 cases of T-ALL showed a deletion involving the SCL/tal-1 gene in nine cases. These results suggest that protein expression is not dependent on derangement of the SCL/tal-1 gene, because immunohistochemical detection of the protein was noted in the presence and absence of a tal-d1 deletion.
Base Sequence↗