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At least 19 recordsLinked to original sources
PubMed1992

Amplification and expression of the bcl-1 gene in human solid tumor cell lines.

The bcl-1 gene maps to chromosome 11q13 and has recently been shown to be a member of the cyclin gene family. Amplification of the chromosome region containing bcl-1 occurs frequently in breast cancer, squamous cell cancer, and other tumor types. We have hypothesized that amplification results in altered expression of the bcl-1 gene, contributing to carcinogenesis. In this work, we studied bcl-1 gene amplification and expression in a panel of human cell line. bcl-1 is expressed in all cell lines studied. The level of expression tends to be higher in amplified cell lines. We also screened these cell lines for int-2 and hst-1 expression, genes which are frequently coamplified with bcl-1. No int-2 expression was detected, and the two cell lines expressing hst-1 were unamplified. Our data provide support for the importance of bcl-1 in carcinogenesis.

Blotting, Northern↗
PubMed1992

The establishment of an interleukin-6-dependent myeloma cell line (FLAM-76) carrying t(11;14)(q13;q32) chromosome abnormality from an aggressive nonsecretory plasma cell leukemia.

A new myeloma cell line designated FLAM-76 was established from a patient with an aggressive nonsecretory plasma cell leukemia. The cell line exhibited morphologic features of flaming cells and contained an abundant eosinophilic cytoplasm with many dilated cisternae of rough endoplasmic reticulum. FLAM-76 cells were positive for cytoplasmic kappa (kapp)-type immunoglobulin but did not secrete it into the culture medium. The cells proliferated in the presence of exogenous interleukin-6 (IL-6) and more than 800 pg/ml of IL-6 was necessary for their continuous growth. The cells did not grow without IL-6, and they did not produce IL-6. Thus, the growth of FLAM-76 appeared to be regulated by the paracrine mechanism of IL-6. Alpha-interferon (alpha-IFN) inhibited the IL-6-dependent growth of FLAM-76 in doses greater than 1000 U/ml. FLAM-76 cells expressed CD38 (OKT10) and cell adhesion-associated antigens such as CD44 and CD54 (ICAM-1). Chromosome analysis revealed FLAM-76 to have a hypodiploid chromosome constitution with t(11;14)(q13;q32) abnormality, which frequently is seen in neoplasms of B-cell origin. Immunoglobulin (JH and Ck) gene rearrangement (but no BCL-1 gene rearrangement) was found in this cell line.

Aged↗
PubMed1992

Comparison of chromosome analysis and BCL-1 rearrangement in a series of patients with multiple myeloma.

Translocation (11;14)(q13;q32) is a recurring chromosome abnormality which is found non-randomly in non-Hodgkin's lymphoma, especially of follicular type, as well as in B-cell chronic lymphocytic leukaemia, Waldenström's macroglobulinaemia and multiple myeloma. To define further the prevalence of this abnormality in multiple myeloma, we studied a series of 17 patients with this disease with concomitant chromosome analysis and Southern blotting, using a probe specific for the major translocation cluster of the BCL-1 oncogene which is located at chromosome 11q13. Karyotype analysis of 14 evaluable patients revealed three cases with abnormalities of chromosome 11q13, two of them with t(11;14)(q13;q32) and one with del (11)(q13). Southern blot analysis showed no rearrangements in BclI and HindIII digests of DNA from 17 patients including the three patients with anomaly of chromosome 11q13, using a BCL-1 specific probe. A possible restriction length polymorphism was detected in EcoRI cut DNA of five out of 11 patients studied. Therefore the chromosomal break point in our cases with abnormality of chromosome 11q13 must lie outside the major translocation cluster of the BCL-1 gene. However, in centrocytic lymphoma rearrangement of the BCL-1 oncogene has been detected in up to 50% of cases. Location of the break point may therefore be dependent on the differentiation of the transformed B-cell.

Adult↗
PubMed1992

Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes.

Chromosomal translocation within B and T cell malignancies has proven a rich source for proto-oncogenes. The obligate DNA breaks within immunoglobulin (Ig) and T cell receptor (TCR) loci are frequently the sites of recurrent translocations. Burkitt's lymphoma established the paradigm by introducing the myc oncogene from chromosome segment 8q24 into the Ig heavy chain gene locus at 14q32. Molecular cloning of an aberrant Ig rearrangement in follicular lymphoma revealed Bcl-2. Bcl-2 constitutes the first member of a new category of oncogenes: regulators of programmed cell death. Bcl-2 blocks apoptosis and maintains long-term immune responsiveness including B-cell memory. The PRAD1 gene of parathyroid adenomas appears to be the elusive Bcl-1 gene of t(11;14)(q13;q32) bearing lymphomas. It proves to be a novel G1 cyclin. Acute lymphoblastic leukemias (ALL) pre-B phenotype produce a E2A/PBX fusion protein that possesses the leucine zipper of E2A with the homeodomain of PBX. Two molecular forms of the BCR/ABL fusion protein are produced by the Philadelphia chromosome. A deregulated p210 tyrosine kinase is found in chronic myelogenous leukemia, while a p190 form predominates in Ph+ ALL. In contrast, T-cell ALLs introduce a potpourri of genes into their T cell receptor loci. However, a common theme is emerging. These oncogenes (Ttg1, Ttg2, SCL, LylI, H0X11) all belong to classic families of transcription factors, possessing LIM domains, helix-loop-helix motifs, or homeodomains. Provocatively, these transcription factors are normally intended for lineages other than T cells. These genes have widened the horizons of both oncogenesis and normal development.

Genes, Immunoglobulin↗
PubMed1992

Histogenetic correlations between subcategories of small noncleaved cell lymphomas.

To assess the biologic relevance of the morphologic distinctions between subtypes of small noncleaved cell lymphomas (SNCL), ie, the sporadic Burkitt's type (sBT) and the non-Burkitt's type (nBT), we have examined the molecular organization of several lymphomagenic oncogenes (c-myc, bcl-1, bcl-2) and the potential pathogenetic contribution of the Epstein-Barr virus (EBV). Twenty-nine cases of SNCL, not associated with immunodeficiency syndromes, were reviewed and classified as sBT (18 cases) or nBT (11 cases) without knowledge of the clinical or molecular data. Southern blot analysis of 18 sBTs found 17 to contain c-myc rearrangements. Fifteen of these comigrated with an Ig heavy-chain gene segment, indicating t(8;14) translocation. Chromosome 8 breakpoints were clustered in the first exon and the first intron of the c-myc gene. Chromosome 14 breakpoints mapped to the JH locus in three tumors, the S mu locus in nine tumors, and the S alpha locus in the remaining three tumors. Cases involving the S alpha locus appeared to have a more rapid clinical course. All sBTs possessed germline bcl-2 and bcl-1 gene fragments. In contrast, Southern blot analysis of 11 nBTs found none with c-myc rearrangements. Rather, three of 10 evaluable nBTs had bcl-2 rearrangements. The remaining seven showed no evidence of involvement by any of the lymphoma-associated oncogene/breakpoint regions studied. EBV genome was detected in two sBTs and in one nBT, and thus was not a distinguishing feature. These results indicate that the subtle histologic differences that distinguish subcategories of SNCL are significant biologically and reflect distinct molecular mechanisms of lymphomagenesis. Furthermore, the data suggest that the nBTs comprise a heterogeneous group with respect to their molecular genetic composition and confirm the remarkable molecular genetic homogeneity of the sBT group.

Adolescent↗
PubMed1992

[Molecular-genetic evaluation of translocation of bcl-2 gene and locus bcl-1 in selected lymphoproliferative changes].

In the work it has been decided to evaluate the occurrence of locus bcl-1 rearrangement in type B chronic lymphatic leukemia and that of gene bcl-2 in non-Hodgkin's lymphoma with diffuse morphology, as well as in reactive lymph nodes. The study material comprised DNA isolated from fragments of lymph nodes sent for routine diagnostic examinations at the Institute of Pathology--Pomeranian Medical Academy. Southern's method was used to examine DNA having been cut with restrictive enzymes, estimating the distribution of gene bcl-2 and locus bcl-1. Resorting to Polymerase Chain Reaction (PCR) translocation t (14;18) was assessed by means of short nucleotides hybridizing with 14 and 18 chromosome sequences restricting this translocation. The amplification product was subsequently studied by Southern's method with probe bcl-2. In 1 out of 18 examined cases of type B chronic lymphocyte leukemia it was disclosed that locus bcl-1 had been rearranged. In 45 cases of non-Hodgkin's lymphoma with diffuse morphology the gen bcl-2 was found to display germline arrangement. Germline position of gen bcl-2 was also revealed in 60 cases of reactive lymph nodes.

Blotting, Southern↗
PubMed1992

Mantle cell lymphoma: an update.

Mantle cell lymphoma is a distinctive pathologic entity that incorporates the previous histopathologic categories of centrocytic lymphoma and lymphocytic lymphoma of intermediate differentiation. These lymphomas are characterized by common histologic and immunologic characteristics that suggest derivation from the follicular mantle zone. Mantle cell lymphomas are characterized by the t(11;14) (q13;q32) translocation and its molecular counterpart bcl-1 rearrangement. This translocation activates a gene called BCL-1/PRAD-1. The identification of the BCL-1 gene product as a cyclin has added a new dimension to our understanding of the variety of mechanisms involved in lymphomagenesis.

Antigens, CD↗
PubMed1992

Characterization of chromosome 11 translocation breakpoints at the bcl-1 and PRAD1 loci in centrocytic lymphoma.

The chromosome 11q13 bcl-1 locus is rearranged in the majority of centrocytic lymphomas, a CD5-positive B-cell non-Hodgkins lymphoma, as a result of reciprocal translocation with the 14q32 immunoglobulin heavy chain genes. Although several 11q13 bcl-1 breakpoint sites have been characterized, a postulated bcl-1 oncogene was not identified. Recently, however, a gene encoding cyclin D1, designated PRAD1, was proposed as a candidate bcl-1 oncogene; accumulated evidence now indicates this gene is bcl-1. To further characterize 11q13 breakpoints in B-cell neoplasms, we analyzed 26 centrocytic lymphomas and 68 other B-cell cancers by Southern blot using a panel of breakpoint probes spanning 110 kilobases of the bcl-1 and PRAD1 loci. Nineteen centrocytic cases (73%) showed rearrangement, 15 at bcl-1 breakpoint sites and 5 at PRAD1 sites. One case was rearranged at both bcl-1 and PRAD1 loci. All but the latter case showed comigration of rearranged bcl-1 or PRAD1 bands and immunoglobulin heavy chain joining gene bands, consistent with the t(11;14). bcl-1 rearrangement was present in only one of 68 noncentrocytic B-cell neoplasms; none showed PRAD1 rearrangement. Thus, bcl-1 and PRAD1 rearrangement is strongly associated with centrocytic lymphoma, providing a useful molecular marker for classifying this subtype of lymphoma and suggesting an important role for PRAD1 cyclin D1 in the pathogenesis of this neoplasm.

Chromosomes, Human, Pair 11↗
PubMed1992

[Overexpression of PRAD1 gene in B-cell malignancy with t(11;14)(q13;q32) translocation].

PRAD1 (parathyroid adenoma 1) gene at chromosome 11q13 has been cloned from parathyroid adenomas as a putative oncogene, activated by translocation with the parathyroid hormone gene. 4.5 kb and 1.7 kb mRNA are transcribed and both have the same open reading frame of 885 bp encoding 34 kd protein of a cyclin gene family, cyclin D1. Recently, overexpression of PRAD1 gene has been reported to be correlated closely with the rearrangement of bcl-1 locus, particularly in centrocytic lymphoma. In our study, overexpression of PRAD1 gene was shown in five B cell lines with t(11;14)(q13;q32) including one centrocytic lymphoma line and 4 myeloma lines, when compared with other hematopoietic cell lines without translocation. One of the cell lines, SP-49, demonstrated a truncated mRNA of 3.4 kb, in addition to 1.7 kb of normal size. Southern blot analysis demonstrated a rearrangement with PRAD1 cDNA probe, suggesting that the gene is altered in this particular cell line. By cloning analysis, we confirmed that 1.8 kb deletion in 3' region of PRAD1 gene eliminating the destabilizing signal of PRAD1 mRNA, gave rise to the aberrant mRNA of 3.4 kb. These findings suggest that PRAD1 gene is most likely the candidate oncogene for bcl-1 activated by t(11; 14)(q13;q32) translocation. The gene alteration found in one cell line, SP-49, might also play an important role for deregulation of the gene.

Adenoma↗
PubMed1992

PRAD1 (cyclin D1): a parathyroid neoplasia gene on 11q13.

Hyperparathyroidism is a central component of multiple endocrine neoplasia type 1 (MEN 1), and both sporadic and familial forms of parathyroid disease may share certain pathogenetic features. We recently identified a gene that is clonally rearranged with the PTH locus in a subset of sporadic parathyroid adenomas. This candidate oncogene, PRAD1 (previously D11S287), appears to contribute to parathyroid tumorigenesis in a fashion analogous to activation of C-MYC or BCL-2 by rearrangement with tissue-specific enhancers of the immunoglobulin genes in B-lymphoid neoplasia. The PRAD1 gene maps to 11q13 and has been linked to the BCL-1 breakpoint locus, although not to the most tightly linked MEN 1 markers, by pulsed field gel electrophoresis. PRAD1 may, in fact, be the long-sought BCL-1 lymphoma oncogene. PRAD1 encodes a novel type of cyclin protein and thus may normally function in controlling the cell cycle, perhaps through direct interaction with cdc2 or a related kinase. PRAD1's possible primary, or more likely secondary, involvement in the pathogenesis of MEN 1-related tumors is unknown and under investigation.

Amino Acid Sequence↗
PubMed1992

Analysis of c-myc, bcl-1 and bcl-2 translocations in human lymphoma by pulsed-field gel electrophoresis.

Translocations of the c-myc, bcl-2 and the putative bcl-1 oncogene are recurrent events in B-cell lymphoma. Since it is likely that the rearranged genes contribute to the malignant phenotype of the tumor cells, such oncogene translocation is of major interest. The molecular detection of translocations using conventional Southern hybridization analysis is complicated by the fact that translocation breakpoints are dispersed over large chromosomal regions. In order to overcome this problem we used pulsed-field gel electrophoresis (PFGE) to detect c-myc, bcl-2 and bcl-1 translocations in 29 lymph node biopsies. C-myc translocation could not be detected in this group, either with standard Southern analysis of PFGE. Translocations of the bcl-2 gene were detected by PFGE in 5 samples and the breakpoints were mapped in all cases to the third exon of bcl-2 by standard Southern analysis. Furthermore, we also found rearrangements of the bcl-1 locus in 3 samples. Mapping of the breakpoint failed in one of these cases, which strongly indicates the existence of a breakpoint outside the bcl-1 major breakpoint region. Thus, PFGE allows the rapid detection of translocations in human lymphomas within large stretches of DNA.

Adult↗
PubMed1992

Detection of oncogene rearrangements in human non-Hodgkin's lymphomas.

Southern blot hybridization was used to detect the rearrangement and amplification of five proto-oncogenes (bcl-2, bcl-1, c-myc, c-myb and c-Ha-ras) and one tumor suppressor gene (RB-1) in 55 Japanese patients with non-Hodgkin's lymphoma; 16 with T-cell lymphomas and 39 with B-cell lymphomas (7 follicular and 32 diffuse lymphomas). Genetic abnormalities of the proto-oncogenes were detected in 7 of the 55 (13%). Genetic abnormalities of bcl-2 plus other genes were detected in 5 of 7 cases of follicular lymphoma (71%), rearrangements of bcl-2 and c-myc, rearrangement of bcl-2 and amplification of c-myb. Genetic abnormalities were observed in only three cases of diffuse lymphoma. In each of 3 cases of B-cell lymphoma, one of the genes, blc-2 mbr, bcl-2 mcr and c-myc, was rearranged respectively. The incidence of genetic abnormalities in diffuse lymphomas (6.3%) was lower than that in follicular lymphomas. None of diffuse lymphomas had double oncogene abnormality. No abnormalities were found in RB-1, bcl-1, and Ha-ras. These findings suggest that follicular lymphomas are associated with some abnormalities of oncogenes not restricted to bcl-2 that facilitate growth which may be associated with their clinical features.

Blotting, Southern↗
PubMed1992

[Oncogenes and their significance for head and neck cancers].

During the past few decades medical science has accepted the concept that cancer is a fundamental disorder of cellular growth control. A disorder can originate in some cells through changes in genes (DNA level: gene amplification, mutation and rearrangement) or their expression (RNA and protein levels), and stimulates growth in contrast to surrounding cells. Over the last decade genes affected in the cancer cell have been identified as well as the nature of changes undergone. Only a few of the known oncogenes play a role in head and neck cancer. These are epidermal growth factor receptor, c-myc, the ras gene family, int-2, hst-1 and bcl-1. In some clinical disorders, such as childhood neuroblastoma and breast cancer, oncogenes have been shown to play an important role in tumor staging or as a prognostic parameter. The aim for future therapy is the effective application of oncogenes (or "gene therapy") in clinical practice.

Animals↗
PubMed1992

Oncogenes and tumour-suppressor genes in squamous cell carcinoma of the head and neck.

Cancer is now considered to be a multi-hit process which involves a number of aberrant genetic events culminating in malignant transformation. In squamous cell carcinoma (SCC) of the head and neck the action of both oncogenes and tumour-suppressor genes has been identified during the course of the disease. Cytogenetic analysis of these carcinomas has demonstrated chromosomal breakpoints, particularly in the regions of 1p22 and 11q13 together with frequent amplification of the proto-oncogenes in the 11q13 amplicon; int-2, hst-1 and bcl-1. Ras mutations have been infrequently identified in the Western World whereas ras over-expression has been a common finding and may be associated with the early development of head and neck cancer. C-myc over-expression appears to correlate with a poor prognosis for these patients. The tumour-suppressor gene p53 is also thought to be involved in the development of SCC in head and neck tumours and its aberrant expression is associated with a history of heavy smoking and heavy drinking. E-cadherin, a putative tumour-suppressor gene is down-regulated in poorly differentiated head and neck SCC and maybe important in nodal metastasis. A recent study has indicated that the Human Papilloma Virus (HPV 16 and 33) has a role in the aetiology of tonsillar carcinomas and HPV has been shown to produce transforming proteins which bind to and inactivate the p53 tumour suppressor gene. This evidence suggests that the possibility of a viral mechanism for the development of SCC in the head and neck should be considered. This paper proposes a series of genetic events to explain the development of SCC of the head and neck.

Cadherins↗
PubMed1992

Differential expression of a CD45R epitope(6B2) on murine CD5+ B cells: possible difference in the post-translational modification of CD45 molecules.

Although murine peritoneal B cells were homogenously positive for an epitope Lp-2, coded for by the alternative exon 4 of the CD45 gene, they were heterogenous with respect to the expression of another CD45R epitope, 6B2, of unknown exon dependency. While the majority of 6B2-high peritoneal B cells was composed of CD5- B cells, those with low or negative 6B2 were CD5+ B cells. Both 6B2+ and 6B2- peritoneal B cells expressed mainly the same largest CD45R transcripts, with all three alternative exon (4, 5, and 6) sequences. Further, a CD5+ B lymphoma cell line, BCL-1, which was found to be Lp-2+6B2- also had the largest isoform of CD45R molecules with all three alternate structures. Although enzyme digestion studies suggested that the 6B2 epitope resides in protein, not in sugar structures, it is likely that a post-translational modification of CD45R molecules is responsible for the presence or absence of 6B2 epitope expression on peritoneal CD5+ B cells. This event may be related to the differential role of CD45R molecules in regulating lymphocyte function.

Animals↗
PubMed1992

Chromosome 11q rearrangements in B non Hodgkin's lymphoma.

The clinical features, morphology and immunophenotype of 20 cases of B non Hodgkin's lymphoma (B-NHL) with chromosome abnormalities involving 11q13-14 were studied, to determine if this abnormality was closely associated with a specific sub-type of B-NHL. A t(11;14)(q13;q32) was found in 11 cases of intermediately differentiated lymphocytic lymphoma (IDLL). A breakpoint in the major translocation cluster of the BCL-1 locus was found in six of these cases. These patients were male with lymphomatous involvement of the bone marrow, marked splenomegaly and frequently had mucosa associated lymphoid tissue involvement. One patient with IDLL had a t(8;11)(p21;q13) and a rearranged BCL-1 locus, suggesting that this may be a variant of t(11;14)(q13;q32). Diagnoses of IDLL, chronic lymphocytic leukaemia, lymphoplasmacytic lymphoma and monocytoid B cell lymphoma were made in all but one of the remaining cases. These cases had either a translocation involving 11q13-14 and various partner chromosomes or an 11q13 deletion. This study demonstrates that 11q abnormalities occur mainly in a group of low-grade B-NHL of non follicle centre cell lineage.

Aged↗
PubMed1992

Detailed analysis of an amplified region at chromosome 11q13 in malignant tumors.

We have examined the amplification unit at chromosome band 11q13 in 12 primary tumors and one cancer cell line (A431) with 15 DNA markers. The amplified region and size varied from one tumor to another; the smallest amplicon was estimated to be 700 kb long and the largest was 4.5 Mb long at maximum, on the basis of a physical map. Furthermore, the DNA amplified in tumors was not always continuous, because in three cases one locus within the amplicon was not amplified. The amplified region common to all 13 cancers consisted of 500 kb of DNA which incorporated eight defined loci (BCL-1, cCI11-524, cCI11-283, cCI11-234, HBI-1, cCI11-454, HSTF1, and INT2). As two of them, cCI11-524 and cCI11-454, were found to contain DNA sequences conserved in other species, one or both of these loci might encode the gene(s) that may be associated with progression of these tumors.

Blotting, Southern↗