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J Cossman

Publications and source records attributed to J Cossman.

At least 55 records · Page 3Linked to original sources
PubMed1990

T-cell receptor gene rearrangements and the diagnosis of human T-cell neoplasms.

The rearranging antigen receptor genes of lymphoid cells serve as unique clonal markers of lymphoid neoplasms. Gene rearrangement analysis is a highly sensitive and reproducible tool which is useful in the diagnosis and classification of malignant lymphoma/leukemia. Although clonality can often be determined among B cell neoplasms by virtue of immunoglobulin isotype analysis, no such phenotypic marker of clonality exists for T cells. Therefore, clonality of T lymphoproliferative processes is most readily determined by rearrangement analysis of the T cell antigen receptor genes. The alpha, beta, gamma, and delta genes of the T cell receptor gene family encode heterodimeric surface antigen receptors and undergo rearrangement early in T cell differentiation. Identification of rearrangement of T cell antigen receptor genes provides valuable diagnostic information concerning cellular lineage, clonality and classification of T cell neoplasms. This molecular approach is applicable to the diagnosis of occult disease, relapse, and resolution of diagnostic dilemmas in any type of tissue sample including fluids and needle aspirations.

Gene Rearrangement, T-Lymphocyte↗
PubMed1990

Molecular genetics and its application to the diagnosis and classification of hematopoietic neoplasms.

Diagnostic pathology and hematology have been enormously helped by recent advances in laboratory techniques that enable sensitive detection and more accurate and reproducible classification of lymphoproliferative processes. This review will focus on the normal molecular mechanisms that lead to the generation of immunocompetence. In addition, some of the techniques of recombinant DNA technology that can be applied to the diagnosis and classification of hematopoietic neoplasms will be described. These common DNA techniques can be of great help in the following problems: differentiation of monoclonal (usually malignant) from polyclonal (usually benign) processes, assistance in differentiation of malignant hematopoietic neoplasms from other poorly differentiated malignant neoplasms of nonhematopoietic lineage such as melanoma or carcinoma, determination of cell lineage (i.e., T lymphocyte versus B lymphocyte), and identification of cytogenetic abnormalities such as chromosomal translocations. From these cytogenetic abnormalities probes may be constructed and used to substitute for the more labor-intensive, technically demanding conventional microscopic karyotype.

Genetic Techniques↗
PubMed1990

Mechanism of bcl-2 activation in human follicular lymphoma.

The t(14; 18) chromosomal translocation of human follicular lymphoma recombines the bcl-2 gene from chromosome 18 with the immunoglobulin heavy chain joining region. In the t(14; 18) translocation bearing cell line SU-DHL-6, this results not only in an inappropriately high rate of bcl-2 transcription for a mature B cell, but also in two potentially critical point mutations. To determine the relative importance of these mutations, we searched for their presence in DNA from the involved lymph nodes of 12 patients with t(14; 18) follicular lymphoma. bcl-2 genomic sequences were specifically amplified by the polymerase chain reaction technique and then directly sequenced. None of the 12 samples analysed revealed the codon 7 or codon 129 mutation detected in SU-DHL-6. We conclude that abnormal expression of bcl-2 rather than structural alterations at codon 7 or 129 play an important role in the disordered growth and differentiation of follicular B-cell lymphoma.

B-Lymphocytes↗
PubMed1989

Gamma/delta lineage relationship within a consecutive series of human precursor T-cell neoplasms.

We analyzed the gene rearrangements associated with the newly described delta T-cell receptor (TCR) gene from a series of 19 consecutive precursor T-cell (lymphoblastic) neoplasms that represent discrete stages surrounding the TCR gene rearrangement process. Significantly, the delta TCR gene showed rearrangement in most (13 of 19) of these T cells, and in addition it was rearranged in two cells displaying no rearrangement for any other TCR gene. Our survey showed three types of delta gene rearrangements associated with cell-surface TCR expression that presumably represent usage of three V delta genes. This analysis demonstrates (1) a major subclass of human precursor T-cell neoplasms belonging to the gamma/delta T-cell receptor-rearranging subtype; (2) a narrow repertoire of human V delta gene usage; and (3) the utility of delta gene rearrangements as a diagnostic clonal marker in precursor T lymphoblastic neoplasms.

Amino Acid Sequence↗
PubMed1989

Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors.

The development of multidrug resistance in MCF-7 human breast cancer cells and the acquisition of broad resistance to xenobiotics in rat hyperplastic nodules are both associated with increased P-glycoprotein (mdr) gene expression as well as changes in activities of intracellular detoxication enzymes; among these changes is a significant increase in the activity of the anionic isozyme of glutathione-S-transferase (GST). We have isolated a cDNA encoding the human anionic glutathione-S-transferase, GST pi-1, from a cDNA library constructed from multidrug-resistant MCF-7 cells. The deduced amino acid sequence of GST pi-1 shows that while the human anionic GST displays 85% nucleotide and amino acid sequence homology to the rat anionic isozyme, it is markedly less related to human basic GST isozymes. We have examined the expression of GST pi and P-glycoprotein in 170 specimens of human tissues and tumors. P-Glycoprotein RNA expression was positive in eight of 23 lymphomas and two of 12 colon tumors; however, many other normal and malignant tissues, including lung, bladder, and breast tumors, had low or undetectable levels of P-glycoprotein RNA expression. In contrast, GST pi was readily detected in a wide variety of normal and malignant tissues. The level of GST pi mRNA expression in normal tissues was heterogeneous, with lowest levels found in liver and the highest levels found in lung, esophagus, and placenta. GST pi was also variably expressed in human tumors, with the lowest relative levels occurring in lymphoma and breast cancer and the highest levels found in lung cancer and head and neck tumors. In addition, comparison of paired specimens from the same patient indicated that GST pi expression was increased in many tumors relative to matched normal tissue.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Variant translocation of the bcl-2 gene to immunoglobulin lambda light chain gene in chronic lymphocytic leukemia.

The bcl-2 gene has been identified as a gene directly involved in the consistent chromosome translocation t(14;18), which is found in approximately 90% of human follicular lymphoma cases, and is a prime candidate for the oncogene playing a crucial role in follicular lymphomagenesis. In this paper, we describe a case of chronic lymphocytic leukemia showing the juxtaposition of the bcl-2 gene on chromosome 18 to immunoglobulin lambda light chain (Ig lambda) gene on chromosome 22 in a head-to-head configuration. Sequencing analysis of the joining site of the bcl-2 gene and Ig lambda gene has shown that the breakpoint is within the 5' flanking region of the bcl-2 gene and about 2.2 kilobases 5' to the joining segment of Ig lambda locus in a germ-line configuration. The extranucleotide, commonly appearing at the joining site of the t(14;18) translocation involving the IgH locus, is absent from the joining site of bcl-2 and Ig lambda. The lack of extranucleotide suggests that the juxtaposition of the bcl-2 and Ig lambda genes occurred during physiological rearrangement of the Ig lambda gene since it has been shown that the rearrangement of the Ig lambda locus is not accompanied by extranucleotides.

Base Sequence↗
PubMed1988

Stable T3- and T3+ subclones derived from the mosaic human T cell leukemia cell line, CEM.

An unexplained feature of the human T lymphoblastic leukemia cell line, CEM, is a heterogeneous expression of surface membrane T3-TCR complex. CEM cells constitutively maintain two distinct populations whereby a minority of cells (5 to 16%) express T3 but the remainder do not. From the parental cell line, we have derived stable subclones in which all cells express surface T3 and companion subclones that lack surface T3. Inasmuch as surface T3 expression is contingent on assembly and coexpression of the multichain T3 protein complex with the TCR, we compared the surface T3+ and T3- subclones for their rearrangement and expression of genes of the T3-TCR complex. Restricted DNA of both subclone types showed the identical monoclonal pattern of TCR gene rearrangement seen in the mosaic parental CEM line. Northern blot analysis revealed mRNA transcripts of TCR beta subunit and T3 delta in both the surface T3+ and T3- subclones. However, surface T3+ subclones transcribed abundant full length (1.5-kb) TCR alpha mRNA in contrast to the surface T3- subclones in which TCR alpha transcripts were undetectable. Lack of TCR alpha gene transcription was not attributable to either unrearranged or aberrantly rearranged TCR alpha genes because exposure of surface T3- cells to phorbol ester induced a rapid (15-min) and progressive accumulation of full length (1.5-kb) TCR alpha mRNA. This was followed by surface membrane T3 expression in 24 to 72 h. We conclude that the unusual phenotypic mosaicism of CEM cells is attributable to a reversible lack of transcription of the TCR alpha gene.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Molecular pathways of adhesion in spontaneous rosetting of T-lymphocytes to the Hodgkin's cell line L428.

Spontaneous rosetting of T-lymphocytes to Reed-Sternberg cells has been observed both in vitro and in vivo but its molecular mechanism has not been defined. We have investigated such rosetting using the Hodgkin's cell line L428. L428 expresses high levels of LFA-3 and ICAM-1, both of which are ligands for T-cell adhesion. Monoclonal antibody inhibition of spontaneous rosetting indicated that it is not dependent on the T-cell receptor complex but is largely mediated by interaction of T-cell CD2 (T11/E-rosette receptor) with its ligand LFA-3 on L428 cells. Studies using an alternate assay of adhesion (conjugate formation) confirm the roles of CD2/LFA-3 and also implicate a second mode of binding via LFA-1 on T-cells to ICAM-1 on L428. These data explain the previously reported finding of T-cell rosetting with Reed-Sternberg cells as an exaggeration of normal antigen-independent T-cell adhesion.

Antibodies, Monoclonal↗
PubMed1988

Retrospective analysis of stage I and II indolent lymphomas at the National Cancer Institute.

We have retrospectively reviewed the records of 54 patients with Stages I and II indolent lymphoma treated at the National Cancer Institute between January 1958 and December 1984. Patients were treated by a variety of approaches, with 48/54 patients receiving some form of radiation therapy. The median potential follow-up was 9 years (rang 1.7-23.7 years). Overall survival and disease-free survival at 10 years were 69% and 48%, respectively. There were no relapses among Stage I patients after 6.5 years, with 11 of 27 patients followed beyond that time, suggesting that some patients may be cured. Of the 38 patients who received radiation therapy alone as primary treatment, 17 ultimately relapsed. Seventy-one percent of these relapses were nodal. Our data suggest that patients with early stage indolent lymphoma can be treated with curative intent. The finding that most relapses after radiation therapy occur in untreated lymph nodes suggests that total lymphoid irradiation may prolong disease-free survival and, perhaps, overall survival as well.

Adolescent↗
PubMed1988

NIH conference. Angioimmunoblastic lymphadenopathy with dysproteinemia.

Angioimmunoblastic lymphadenopathy with dysproteinemia is a disorder characterized by a sudden onset of constitutional symptoms and lymphadenopathy. Patients often have hypergammaglobulinemia, autoantibodies, rashes, thrombocytopenia, or hemolytic anemia. Diagnosis requires a lymph node biopsy that shows architectural effacement, absence of germinal centers, arborization of postcapillary venules, and a polymorphous infiltrate that includes immunoblasts. Early in the disease, activated T cells in blood and lymph nodes stimulate B cells to proliferate and produce antibody. However, late in the disease, immune suppression may result from increased suppressor function. Clonal rearrangements, which are seen in all patients with regard to either the T-cell receptor beta-chain gene or immunoglobulin genes, have been followed by malignant transformation and frank lymphoma in some patients. Thus, this disorder stands partway between benign lymphoid proliferation and clonal lymphoid transformation. The prognosis of this disorder is poor; 75% of patients die within 2 years or develop a lymphoid malignancy. The rest usually go into a sustained remission. Current treatment with corticosteroid and immunosuppressive agents is unsatisfactory, especially because of late immunosuppression and predisposition to infections.

Blood Protein Disorders↗
PubMed1988

Molecular genetics and the diagnosis of lymphoma.

Gene rearrangement analysis has emerged as a precise laboratory aid in the diagnosis and classification of malignant lymphoma and leukemia. Both clonality and lineage can be identified in lymphoid neoplasms by the demonstration of rearrangements of antigen receptor genes of the immunoglobulin supergene family--immunoglobulin and T-cell receptor genes. Rearrangement analysis is not only useful in differential diagnosis and classification, but also serves as a sensitive unique clonal marker to detect early occult recurrence in patients after therapy. In a similar manner, chromosomal translocations associated with specific disease types can be detected with DNA probes in Southern blot analysis without the use of conventional cytogenetics. Using this approach, one may diagnose specific chromosomal translocations associated with histologic types of lymphoma and leukemia. When appropriately applied, DNA rearrangement analysis complements conventional histology, immunophenotyping, and cytogenetics.

Biomarkers, Tumor↗
PubMed1988

Diagnostic interpretation of T gamma gene rearrangement: effect of polyclonal T cells.

Rearrangement of the T gamma gene, which encodes one chain of the second T-cell receptor, is an early event in the development of T lymphocytes. In contrast to the T-cell receptor beta chain gene, the T gamma gene contains a very limited V region gene repertoire, accounting for only 8 to 10 rearranging V gamma genes. As a consequence of the limited number of V gamma genes, only seven or eight nongermline restriction fragments are displayed, even by highly polyclonal T cells. Here, we demonstrate that T gamma gene analysis produces a picture of pseudoclonality among polyclonal T lymphocytes accompanying B-cell lymphoma, T-cell lymphoma, and Hodgkin's disease. As little as 10% contamination by polyclonal T lymphocytes is sufficient to detect rearrangements in both clinical samples and in a controlled sensitivity assay. Conversely, polyclonal T cells were found to obscure T-cell clones when polyclonal T cells represented as little as 30% of total cells. We conclude that, due to the unusual genomic structure of the T gamma gene, rearrangement analysis of the T gamma gene carries a significant limitation as a marker of clonality and lineage.

B-Lymphocytes↗
PubMed1988

Lymphocyte predominant Hodgkin's disease nodular subtype with coexistent "large cell lymphoma". Histological progression or composite malignancy?

Nodular lymphocyte predominant (NLP) Hodgkin's disease (NLP HD) has been recently suggested to be of B-cell derivation on the basis of phenotypic and morphologic findings. Consistent with this view, there are sporadic case reports of coexisting NLP HD and large cell lymphoma (LCL). We describe a compilation of seven unique cases of NLP HD selected from the NIH case consultation files in which lymphohistiocytic mononuclear variant cells (L&H) became clustered into increasingly large aggregates. In areas of the same tumor mass, large confluent sheets of these cells resembled LCL. In contrast to what would be expected for LCL, all patients had localized disease clinically, and six of seven achieved long-term disease-free survival following radiation therapy or chemotherapy (two cases) for HD. None of the patients developed disseminated LCL. Also notable was a high frequency of axillary lymph node involvement (five of seven) and the high rate of occurrence in blacks (six of seven). Immunophenotypic (in two cases) and molecular genetic analysis (in one case) was suggestive of B-cell derivation for the proliferating cells. These findings also raise the possibility that some so-called large cell lymphomas may actually represent histologically progressed NLP HD, and that such cases might be associated with a favorable prognosis comparable to that seen in NLP HD.

Adult↗
PubMed1988

Detection of occult follicular lymphoma by specific DNA amplification.

To detect occult lymphoma, the polymerase chain reaction (PCR) technique was used to amplify joined bcl-2/JH DNA sequences at the juncture of the t(14:18) translocation in follicular lymphoma. Using the heat-stable DNA polymerase Taq and automated cycling of the reaction, we were able to detect as few as one to two copies of bcl-2/JH. Under these conditions, PCR proved to be at least 10,000-fold more sensitive than either conventional flow cytometry or Southern blot restriction analysis. In addition, genomic DNA sequences of four lymphomas confirmed that the size of the amplified segment serves as a tumor marker. Direct application of PCR to patient staging revealed occult malignant lymphoma in tissue otherwise considered uninvolved by standard criteria. We conclude that the striking enhancement in diagnostic sensitivity attained by DNA amplification can serve as a valuable adjunct to the staging and clinical monitoring of follicular lymphoma.

Chromosomes, Human, Pair 14↗
PubMed1988

Detection of human B-lymphotropic virus (human herpesvirus 6) sequences in B cell lymphoma tissues of three patients.

A survey for HBLV (human B-lymphotropic herpesvirus or human herpesvirus 6) sequences by Southern blot analyses was performed on DNA obtained from a variety of pathologically defined tissues, including a number of lymphomas, leukemias, and tissues from other hematologic disorders. Of the over 50 specimens studied, viral sequences were detected in three lymphomas of B cell derivation: an Epstein-Barr virus-positive African Burkitt's lymphoma, a follicular large cell lymphoma (nodular histocytic lymphoma), and two Epstein-Barr virus-negative tumors from a patient with Sjogren's syndrome. These results are the first indication of HBLV sequences associated with B cell tumors in a limited number of cases and raise the possibility that the virus might be involved in the genesis of some B cell tumors.

Aged↗