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J Sklar

Publications and source records attributed to J Sklar.

At least 91 records · Page 5Linked to original sources
PubMed1988

Single cell origin of bigenotypic and biphenotypic B cell proliferations in human follicular lymphomas.

To investigate the possible relatedness of the subpopulations that make up so-called biclonal lymphomas, we examined five bigenotypic and biphenotypic follicular lymphomas using DNA probes specific for the t(14;18) chromosomal translocation, which is a characteristic feature of these neoplasms. On Southern blot analysis, both subpopulations from four of five lymphomas contained comigrating t(14;18) DNA rearrangements, confirming the single cell origins for these neoplasms. No comigrating t(14;18) DNA rearrangements were observed in the fifth lymphoma, but nucleotide sequence analysis of cloned, breakpoint DNA showed identical t(14;18) crossovers in the two subpopulations. The migration differences of both the Ig and chromosome 18 DNA rearrangements were shown to result from somatically acquired mutations of the Ig genes from the fifth lymphoma. These studies indicate that Ig gene rearrangements and idiotope expression are not consistently stable clonal markers since they are subject to variability as a result of somatic mutation. Although translocated chromosome 18 DNA rearrangements are more reliable, they may also vary among cells of some tumors since somatic mutation can affect, as well, DNA of translocated alleles in follicular lymphomas.

B-Lymphocytes↗
PubMed1988

Large-cell hematolymphoid neoplasms of uncertain lineage.

In almost every large study attempting to characterize non-Hodgkin's lymphomas, there is a small subset of tumors for which the lineage remains poorly defined. The investigators studied a series of 20 hematolymphoid neoplasms that could not be clearly assigned to the B or T cell lineage by phenotypic criteria. Histologically, 12 cases had an appearance suggesting a histiocytic origin, seven cases resembled a pleomorphic immunoblastic lymphoma, and one had a sarcomatoid appearance. By immunologic studies, a variety of B cell, T cell, and monocyte/macrophage markers were expressed on the neoplasms, often with coexpression of markers for different lineages. Twelve cases expressed the Ki-1 antigen. In immunogenotyping studies of T cell receptor (TCR) and immunoglobulin genes, 13 cases showed clonal rearrangements of the beta or gamma TCR gene; one of these cases also had clonal rearrangements of a light chain immunoglobulin gene. Seven cases showed a germline configuration with all combinations of probes and enzymes used. We conclude that a small subset of hematolymphoid neoplasms shows a pattern of diverse immunologic marker expression that does not appear to reflect normal differentiation. However, a majority of these cases contain clonal TCR gene rearrangements, suggesting a frequent relationship to the T lineage.

Adolescent↗
PubMed1988

Applications of antigen receptor gene rearrangements to the diagnosis and characterization of lymphoid neoplasms.

During early stages of lymphocyte development, genes for antigen receptors (immunoglobulin and T-cell receptor proteins) undergo rearrangements of their DNA sequences. The resulting configurations of rearranged DNA are highly variable from cell to cell and serve as genetic markers for individual lymphocytes. These markers can be utilized to detect clonal lymphocytic proliferations, as seen in lymphoid malignancies, and to identify the lineage of lymphoid neoplasms. Chromosomal rearrangements involving recombination between the DNA of antigen receptor genes and other sites in the genome also occur in lymphoid neoplasms, and molecular analysis of such rearrangements is potentially useful in the diagnosis of lymphomas and leukemias.

DNA, Neoplasm↗
PubMed1988

Clonal analysis of transplant-associated lymphoproliferations based on the structure of the genomic termini of the Epstein-Barr virus.

The clonal composition of various transplant-associated lymphoproliferations was assessed by means of Southern blot hybridizations using a DNA probe specific for the fused termini of the Epstein-Barr virus (EBV) genome. A single clonal band representing the joined EBV genomic termini was detected in most biopsies, demonstrating the presence of a monoclonal expansion of B lymphocytes carrying EBV DNA. Different configurations of immunoglobulin gene rearrangements and fused EBV genomic termini were frequently observed in tissues from different biopsy sites in individual patients, confirming the multiclonal origins for these lymphomas. In rare specimens, multiple forms of the joined termini were detected within individual lesions, which appeared polymorphous by histologic methods of analysis and polyclonal by immunologic and immunogenetic methods of analysis. These studies confirm that there is a spectrum of EBV-associated disorders of varying clonal composition that may arise in immunosuppressed organ-allograft recipients. The data are consistent with the proposal that the lymphoproliferations initiate as polyclonal expansions of EBV-carrying B cells, which progress to multiclonal lymphomas in most patients. Detection of homogeneous episomal EBV DNA in most lesions supports a primary role for the virus in the pathogenesis of these disorders.

B-Lymphocytes↗
PubMed1988

Absence of clonal beta and gamma T-cell receptor gene rearrangements in a subset of peripheral T-cell lymphomas.

The authors describe a set of seven peripheral T-cell lymphomas that lack detectable rearrangements of T-cell receptor (TCR) genes. All cases showed antigenic profiles consistent with T-cell lymphoma, including expression of Leu-5 (CD2) antigen. However, few other T-lineage markers were found, and none of the cases tested (6 of 7) bound antibody recognizing the constant region of the beta TCR protein. Each case showed exclusively germline configurations of DNA for the beta TCR genes in Southern blot analyses with the use of several different combinations of restriction enzymes and DNA hybridization probes. One case contained clonal rearrangements of the gamma TCR gene and of the immunoglobulin heavy chain gene. Our results suggest that certain cases of peripheral T-cell lymphoma may lack rearrangements of TCR genes--particularly those cases expressing restricted numbers of T-lineage antigens. In view of these findings, failure to detect rearrangements of TCR genes by Southern blot analyses is not necessarily inconsistent with malignant lymphocytic proliferations in T-lineage neoplasia.

Adult↗
PubMed1987

Molecular analysis of the t(14;18) chromosomal translocation in malignant lymphomas.

One of the most common karyotypic abnormalities is the t(14;18) translocation, which is found in many lymphomas that have a characteristic follicular morphology. Recent molecular studies have shown that this chromosomal translocation results in the juxtaposition of the candidate proto-oncogene bcl-2 (B-cell leukemia-lymphoma) on chromosome 18 with the immunoglobulin heavy-chain locus on chromosome 14. However, because performing accurate cytogenetic studies in solid hematolymphoid neoplasms is difficult, knowledge of the prevalence of the t(14;18) translocation and, by association, the extent of bcl-2 involvement in human lymphomas is limited. We used a number of chromosome-18 DNA probes to analyze various subtypes of Hodgkin's and non-Hodgkin's lymphomas and test for structural abnormalities near or within the bcl-2 gene. Molecular features of the t(14;18) translocation were found in virtually all follicular neoplasms and about 28 percent of diffuse large-cell lymphomas. No changes in bcl-2 were found in several other subtypes of Hodgkin's and non-Hodgkin's lymphomas, including those previously suggested to originate from follicular-center cells and those about which cytogenetic data have been difficult to obtain. Our findings suggest a close pathogenetic relation between bcl-2 and a large group of non-Hodgkin's lymphomas, both with and without a follicular morphology. The methods employed in this study may be useful in improving the accuracy of diagnosis and subclassification of malignant lymphomas.

Chromosome Mapping↗
PubMed1987

Analysis of DNA surrounding the breakpoints of chromosomal translocations involving the beta T cell receptor gene in human lymphoblastic neoplasms.

DNA containing breakpoints of two different t(7;9) chromosomal translocations was cloned from the T lymphoblastic tumor cell lines SUP-T1 and SUP-T3. Sequence analysis of DNA from the t(7;9)(q34;q34.3) translocation of SUP-T1 revealed that chromosome 9 DNA had recombined with DNA 5' to rearranged D-J regions in the beta T cell receptor gene of chromosome 7. Restriction analysis and hybridization studies using DNA fragments cloned from the t(7;9)(q34;32) translocation of SUP-T3 confirmed that beta T cell receptor DNA is also joined to the DNA of chromosome 9 in these cells. Using hybridization probes for the two breakpoints, several other cases of T lymphoblastic tumors were shown to possess DNA rearrangements near the 9q34.3 and 9q32 sites. Hybridization with the 9q34.3 probe detected multiple transcripts in SUP-T1 RNA and small amounts of larger transcripts in T cells lacking the t(7;9)(q34;q34.3) translocation. This work directly demonstrates that the beta T cell receptor locus may frequently be involved in chromosomal translocations within T lymphoblastic neoplasms.

Chromosome Mapping↗
PubMed1987

Establishment and characterization of a common acute lymphoblastic leukemia cell line with a deletion of chromosome 3 band q26.

This paper describes the establishment and characterization of a new cell line (SUP-B7) which was established from a child with "common" acute lymphoblastic leukemia. The SUP-B7 cells (and the patient's tumor) have been characterized by cytochemical staining, monoclonal antibodies, enzyme analyses, gene rearrangement studies, and karyotype analysis. The SUP-B7 cells are periodic acid-Schiff positive, common acute lymphoblastic leukemia antigen positive, and terminal deoxynucleotidyl transferase positive, and they lack the Epstein-Barr virus genome. In addition, the SUP-B7 cells lack cytoplasmic and surface immunoglobulins, and the immunoglobulin gene rearrangement studies showed rearranged heavy chain genes with germ line light chain genes. Concordance between the cell line and the patient's tumor was established by the immunoglobulin gene rearrangement studies. Using Southern blot analysis of the DNA from the patient's tumor and the SUP-B7 cells, there was comigration of the bands representing the rearranged immunoglobulin heavy chain gene. In addition, the SUP-B7 cells possess a single chromosome abnormality: del(3)(q26q28), with the chromosome breakpoint at or near the transferrin receptor gene. Since the SUP-B7 cell line is concordant with the patient's malignancy and since these cells possess a single chromosomal abnormality, the SUP-B7 cell line may be a useful tool in determining the biological significance of the chromosome deletion: del(3)(q26q28).

Antigens↗
PubMed1987

Epstein-Barr virus-transformed B-cell line (DV-1) derived from bone marrow of a patient with severe combined immunodeficiency and immunoblastic lymphoma.

An Epstein-Barr virus-transformed B-cell line derived from a patient with severe combined immunodeficiency who died of a lymphoreticular malignancy has been characterized. The line derived from bone marrow cultures and designated DV-1 shows surface and cytoplasmic IgM and staining with fluorescent monoclonal antibodies against immunoglobulin heavy and light chains mu, delta, and kappa, Dr, and several other B-cell surface antigens. DV-1 secretes IgM kappa and demonstrates monoclonality on analysis of immunoglobulin heavy and light chain gene rearrangement patterns. Incubation with either phytohemagglutinin or pokeweed mitogen failed to cause significant stimulation of proliferation of DV-1 and another EBV-transformed B-cell line derived from an immunologically normal host (LA-350), whereas incubation with Staphylococcus aureus Cowan strain 1 led to significant inhibition of DV-1 and LA-350. Rabbit IgG antibody specific for human immunoglobulin mu-chains produced a dose dependent stimulation of both lines. The responses of DV-1 and LA-350 to mitogens and anti-mu were not as high as those of normal peripheral blood lymphocytes. This spontaneously derived Epstein-Barr virus-transformed B-cell line from a patient with severe combined immunodeficiency demonstrated functional characteristics similar to a B-cell line derived from an immune competent host. While these cells spontaneously incorporate 200 times more thymidine than normal resting peripheral blood lymphocytes, they retain their ability to be modulated by antiimmunoglobulin, and staphylococcal Cowan strain 1, but are unresponsive to the effects of B-cell growth factor.

B-Lymphocytes↗
PubMed1987

Epstein-Barr viral DNA in tissues of Hodgkin's disease.

Tissue specimens from 21 cases of Hodgkin's disease were examined for the presence of Epstein-Barr virus (EBV) and cytomegalovirus DNA by molecular hybridization techniques. EBV DNA was detected in 4 cases, including 2 of 8 cases which had been previously shown to contain clonal immunoglobulin gene rearrangements. Two of the cases containing EBV DNA were of the nodular sclerosing type and had received prior therapy; the other 2 were classified as mixed cellularity Hodgkin's disease and had not received therapy before the biopsy tissue was obtained. Analyses of the terminal portions of EBV genomes indicated a monoclonal or oligoclonal proliferation of EBV-infected cells in the tissues studied. In contrast, none of the 21 cases had detectable cytomegalovirus DNA sequences. The identification of EBV DNA may reflect the proliferation of lymphoblastoid cells due to the reduced immune competence frequently noted in Hodgkin's disease or may indicate the presence of EBV genomes within Reed-Sternberg cells.

Adult↗
PubMed1987

Non-Hodgkin's lymphoma containing both B and T cell clones.

We describe a patient in whom two lymph node biopsies removed 18 months apart disclosed histologic and immunophenotypic evidence of a non-Hodgkin's lymphoma containing neoplastic lymphocytes of both B and T type. Analyses of immunoglobulin and T cell receptor genes confirmed the presence of separate B and T cell clones. In addition, immunogenotyping revealed the possibility of a second B cell clone within the patient's tumor. Development of a multiclonal lymphoma in this patient may relate to the carcinogenic effects of chemotherapy or to a predisposition for neoplastic transformation of lymphocytes due to a previously diagnosed autoimmune condition. Another possible explanation is that the lymphoma implies the existence in this patient of a transformed lymphocyte-committed stem cell that is capable of generating both B and T lineage clones.

B-Lymphocytes↗