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D M Knowles

Publications and source records attributed to D M Knowles.

At least 73 records · Page 4Linked to original sources
PubMed1995

Breast cancer heterogeneity: evaluation of clonality in primary and metastatic lesions.

Breast cancers often contain different clones of tumor cells. Attention to the cellular properties of breast cancer metastases may identify characteristics in primary tumors that are associated with metastasis. Such characteristics could include DNA content, cell proliferation, abnormal oncogene expression, or relative cell population (clonal dominance). We examined DNA ploidy (image analysis), proliferation index (proliferating cell nuclear antigen-1 immunostaining), and expression of Her-2/neu oncoprotein in 17 invasive breast cancer samples (36 primary tumor samples) and 82 corresponding regional metastases. In all samples the primary tumor was multiclonal (usually biclonal) by DNA ploidy analysis. In approximately 90% of metastatic DNA clones (30 of 34) the corresponding clone was identified in a primary tumor sample representing 25% or more of the tumor cell population (significant clone). A majority DNA clone (> or = of tumor cell population) existed in 60% (21 of 36) of primary tumor samples and in 70% (60 of 82) of metastases (30% diploid v 70% nondiploid in both groups). In approximately 50% of metastases (37 of 82) an unexpected majority clone was identified (not a majority in any primary tumor sample) and the ratio of diploid to nondiploid clones also was 30% to 70%. However, in 80% of majority metastatic clones (46 of 60) that clone was a significant primary tumor clone. Proliferation index was quite variable in primary tumor samples and in corresponding metastases. Overexpression of Her-2/neu oncoprotein in the primary tumor of seven of 10 patients also was identified in all corresponding metastases in five of seven patients and in some metastases in two of seven patients. The metastases in three Her-2/neu-negative patients were all negative. We conclude that (1) DNA clones are stable after metastasis, (2) clonal majorities in metastases reflect clones identified in primary tumors, (3) different metastatic clones from an individual tumor can establish clonal majorities, (4) neither diploid nor aneuploid cells have a metastatic advantage in breast cancer, (5) proliferation indices are heterogeneous, and (6) overexpression of Her-2/neu is usually consistent between primary tumors and corresponding metastases.

Breast Neoplasms↗
PubMed1995

Post-transplantation lymphoproliferative disorders arising in solid organ transplant recipients are usually of recipient origin.

Recent clinical, pathological, and molecular studies have increased our understanding of posttransplantation lymphoproliferative disorders (PT-LPDs). Studies have shown that the majority of PT-LPDs arising in bone marrow transplant recipients are of donor origin; however, the source (host or donor) of the lymphoid cells that make up PT-LPDs arising in solid organ transplant recipients has not been systemically investigated. In this study, 18 PT-LPDs occurring in 16 organ transplant recipients (13 heart, 2 kidney, 1 lung), 9 donor tissues (for 10 recipients), and 14 uninvolved recipient tissues (from 12 patients) were examined employing restriction fragment length polymorphism analysis to determine their host or donor origin. The PstI-digested DNAs were analyzed by Southern blot hybridization using two highly informative polymorphic probes that map to chromosome 21 (CRI-PAT-pL427-4) and chromosome 7 (CRI-PAT-pS194). All solid organ PT-LPDs with corresponding uninvolved recipient DNA showed identical hybridization patterns; none of the PT-LPDs exhibited a hybridization pattern that matched donor DNA. These findings suggest that the vast majority of PT-LPDs arising in solid organ transplant recipients, in contrast to those arising in bone marrow transplant recipients, are of recipient origin.

Adolescent↗
PubMed1995

De novo CD5-positive and Richter's syndrome-associated diffuse large B cell lymphomas are genotypically distinct.

Diffuse large B cell lymphomas (DLBLs) represent a heterogeneous collection of aggressive non-Hodgkin's lymphomas that can arise either de novo or as a result of transformation from chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphomas, or lymphomas of mucosa-associated lymphoid tissue. A small percentage of DLBLs express the CD5 antigen. The majority of these cases have evolved from a pre-existing low grade non-Hodgkin's lymphoma (Richter's syndrome). However, we identified and characterized nine CD5-positive DLBLs in which the patients did not have a previous history or concomitant evidence of chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, or mucosa-associated lymphoid tissue-associated non-Hodgkin's lymphoma, suggesting that they arose de novo. All nine cases expressed CD20 and monotypic immunoglobulin, all eight cases examined expressed CD19, CD22 and CD43, eight of the nine cases expressed HLA-DR, and two of eight cases expressed CD11c. None of the cases expressed CD3, CD10, CD11b, CD21, CD23 or CD30. CD5 expression by these cells was found to be identical to that of CD5-positive B cell chronic lymphocytic leukemia by quantitative polymerase chain reaction analysis of CD5 mRNA. These nine de novo CD5-positive DLBLs exhibited clonal immunoglobulin heavy and light chain gene rearrangements but lacked integration of the Epstein-Barr virus genome and structural alterations of the bcl-1, bcl-2, c-myc, H-ras, K-ras, and N-ras proto-oncogenes and the p53 tumor suppressor gene. However, bcl-6 proto-oncogene rearrangement, which is involved in chromosome band 3q27 aberrations, was found in four cases (44.4%). This is comparable with the frequency of bcl-6 gene rearrangement in CD5-negative DLBL. In contrast, bcl-6 gene rearrangement was absent in six cases of DLBL associated with Richter's syndrome. These findings suggest that de novo CD5-positive DLBLs are genotypically similar to CD5-negative DLBLs and may be pathogenetically distinct from the DLBLs associated with Richter's syndrome.

Aged↗
PubMed1994

Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.

Representational difference analysis was used to isolate unique sequences present in more than 90 percent of Kaposi's sarcoma (KS) tissues obtained from patients with acquired immunodeficiency syndrome (AIDS). These sequences were not present in tissue DNA from non-AIDS patients, but were present in 15 percent of non-KS tissue DNA samples from AIDS patients. The sequences are homologous to, but distinct from, capsid and tegument protein genes of the Gammaherpesvirinae, herpesvirus saimiri and Epstein-Barr virus. These KS-associated herpesvirus-like (KSHV) sequences appear to define a new human herpesvirus.

Acquired Immunodeficiency Syndrome↗
PubMed1994

The Reed-Sternberg cells of Hodgkin disease are clonal.

Relatively little progress has been made in understanding the nature of the Reed-Sternberg (RS) cell and its morphologic variants in Hodgkin disease (HD). This is primarily due to the fact that RS cells represent a minute subpopulation within HD lesions. To investigate the clonal origin of RS cells and variants, we studied 27 HD lesions obtained from 11 patients. Using an image analyzer (CAS 200) we were able to demonstrate that CD30-positive RS cells are clonal elements with unique and individualized DNA profiles and that the DNA content of any given patient RS cell population is constant over time and in different pathologic sites. Using 1, 9, 11, and X alpha satellite chromosome probes and interphase cytogenetics, we also demonstrated that RS cells obtained from different tissue samples of the same patient have a unique and often abnormal chromosomal pattern. To definitively prove the hypothesis that CD30-positive RS cells are clonal elements, we investigated the presence of point mutations within p53 gene exons 5 through 9 and found that only a single patient possessed a nonsense p53 somatic point mutation (Arg to His). This same mutation could be identified in all of his available biopsies. Altogether, these findings demonstrate that RS cells and variants in HD are clonal and represent the neoplastic elements of this entity.

Base Sequence↗
PubMed1994

Phenotypic and functional characterization of T-BAM (CD40 ligand)+ T-cell non-Hodgkin's lymphoma.

The precise mechanisms regulating T-helper function have been intensively investigated. We and others have recently identified a new T-cell-B-cell-activating molecule called T-BAM that directs B-cell differentiation by interacting with the CD40 molecule on B cells. Using a specific monoclonal antibody against T-BAM (5C8), we have previously shown that T-BAM expressing T cells are predominantly CD4+CD8- and in normal lymphoid tissue have a unique distribution. However, no information has been obtained regarding the phenotype and functional properties of human neoplastic T cells. Therefore, we investigated T-BAM expression immunohistochemically in 87 well-characterized T-cell non-Hodgkin's lymphomas and lymphoid leukemias (LL). We found that 21/81 neoplasms expressed detectable T-BAM and these positive tumors belong almost exclusively to the CD4+CD8- subtype. In addition, to determine whether T-BAM expression could be induced on T-BAM-LL cells, we activated T-BAM-LLs in vitro and showed that T-BAM could be upregulated only in CD4+CD8- tumors. Our studies clearly show that T-BAM is constitutively expressed in a large number of T-cell neoplasms with a relative mature phenotype (CD4+CD8-) and that only CD4+ neoplastic T cells can be induced in vitro to express this molecule. Additional studies are necessary to identify the biologic significance of T-BAM expression and its potential and clinical implications.

CD4-Positive T-Lymphocytes↗
PubMed1994

Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype.

Acquired immunodeficiency syndrome (AIDS)-associated non-Hodgkin's lymphomas (AIDS-NHL), a major source of morbidity and mortality among AIDS patients, are derived from B cells and can be classified into two main histologic categories, small noncleaved cell lymphoma (SNCCL) and diffuse large-cell lymphoma (DLCL). DLCL includes two histologic subsets, ie, large noncleaved cell lymphoma (LNCCL) and large cell-immunoblastic plasmacytoid lymphoma (LC-IBPL). Several studies have shown that AIDS-SNCCL is associated with the clonal accumulation of multiple genetic lesions, including Epstein-Barr virus (EBV) infection, activation of the c-MYC and RAS oncogenes, as well as inactivation of the p53 tumor suppressor gene at variable frequencies. On the contrary, the molecular pathogenesis of AIDS-DLCL is largely obscure, because no genetic lesion other than EBV infection has been specifically identified in this group. In this study, we have tested a panel of 40 AIDS-NHL for structural alterations of BCL-6, a putative proto-oncogene that is frequently altered in DLCL in the immunocompetent host. Our results show that rearrangements of BCL-6 are present in 20% of AIDS-DLCL (5 of 24), including 2 of 8 LNCCL and 3 of 16 LC-IBPL, but in no case of AIDS-SNCCL. BCL-6 rearrangements were detected both in the presence and in the absence of EBV infection of the tumor clone, but in no case were associated with activation of c-MYC or mutations of p53. These data identify a novel genetic lesion in AIDS-DLCL and corroborate the notion that lymphomagenesis in AIDS follows two distinct molecular pathways that are associated with the development of histologically distinct types of AIDS-NHL.

DNA-Binding Proteins↗
PubMed1994

Molecular characterization of CD30+ anaplastic large-cell lymphoma: high frequency of c-myc proto-oncogene activation.

Anaplastic large-cell lymphoma (ALCL) represents a morphologically distinct type of non-Hodgkin's lymphoma (NHL) characterized phenotypically by the expression of the CD30 antigen, a new member of the nerve growth factor gene family. The lymphoid origin of ALCL has been documented using immunohistochemical and molecular genetic analyses. However, very little is known so far regarding the precise pathogenetic mechanisms involved in its development and progression. Therefore, we investigated bcl-2, p53, and retinoblastoma gene (Rb) expression immunohistochemically; the occurrence of bcl-2, c-myc, and Rb gene rearrangements using Southern blotting; and the presence of ras and p53 gene somatic mutations by single-strand conformation polymorphism assay in a panel of 18 well-characterized ALCLs. In addition, the presence of Epstein-Barr (EBV) and human T-cell lymphotropic virus type I (HTLV-I) genomes were investigated using polymerase chain reaction. We identified abnormal c-myc gene products in 6 of 18 cases (33%) of ALCL. On the other hand, the bcl-2 and Rb genes were not rearranged and K-, N-, and H-ras gene somatic mutations were not found. Significant levels of p53 protein expression were found in more than 60% of ALCLs, but only a single ALCL carried a p53 gene mutation (exon 5). Only 3 ALCL cases, all occurring in human immunodeficiency virus-infected patients, were positive for EBV genomes. On the other hand, contrary to previous findings, no HTLV-I products could be identified. Despite the fact that the c-myc proto-oncogene appears to be frequently altered in ALCL, no pathognomonic abnormality could be identified and therefore additional studies and new strategies should be designed to identify the pathogenetic mechanisms involved in the development of ALCL.

Adolescent↗
PubMed1994

Two acquired immunodeficiency syndrome-associated Burkitt's lymphomas produce specific anti-i IgM cold agglutinins using somatically mutated VH4-21 segments.

We analyzed the reactivity and the structure of the VH and VL segments of two IgM monoclonal antibodies (MoAbs) produced by spontaneously in vitro outgrowing cell lines, HBL-2 and HBL-3, established from two acquired immunodeficiency syndrome (AIDS) patients with Epstein-Barr virus (EBV)-negative Burkitt's lymphoma (BL). These B-cell clones were representative of the respective neoplastic parental clones, as determined by immunophenotypic and molecular genetic analysis. The IgM MoAbs were highly specific for the i determinant on red blood cells (cold agglutinins), but bound none of the other eight self and nine foreign antigens (Ags) tested, including those most commonly recognized by natural antibodies or autoantibodies. Structural analysis showed that the IgM MoAb VH segment sequences were 93.5% and 84.2% identical with that of the germline VH4-21 gene, which encodes the vast majority of cold agglutinins that are specific for the i/l carbohydrate Ag and are produced under chronic lymphoproliferative conditions. The HBL-2 MoAb VH4-21 gene segment was juxtaposed with 20P3 and JH6 genes and paired with a V lambda 1 segment, the sequence of which was 95.5% identical to that of the germline Humlv117 gene; the HBL-3 MoAb VH4-21 gene segment was juxtaposed with DXP'1 and JH5 genes and paired with a V lambda 1 segment, the sequence of which was 86.7% identical to that of the germline Humlv1L1 gene. The high degree of conservation of the VH4-21 gene in the human population, the nature of the nucleotide differences in the expressed VH4-21 segments, and the presence of nucleotide substitutions in the HBL-2 and HBL-3 IgM MoAb JH and/or J lambda segments suggested that the MoAb V segments underwent a process of somatic hypermutation. This was formally shown in the HBL-3 MoAb VH segment, by differentially targeted polymerase chain reaction amplification of the HBL-3 MoAb-producing cell genomic DNA. In addition, cloning and sequencing of the genomic DNA from fibroblasts of the same patient whose neoplastic B cells gave rise to the HBL-3 cell line yielded a germline copy of the VH4-21 gene. Thus, the expression of VH4-21 gene products may be involved in a self Ag-driven process of clonal B-cell expansion and selection associated with BL in these AIDS patients.

Agglutinins↗
PubMed1994

Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma.

The pathogenesis of non-Hodgkin's lymphoma (NHL) with a large cell component (DLLC, including diffuse large cell, DLCL; diffuse mixed cell, MX-D; and immunoblastic, IMB) is unknown. A novel candidate proto-oncogene, BCL6, that is involved in chromosome band 3q27 aberrations in NHL has been recently identified. We have investigated the incidence and disease-specificity of BCL6 rearrangements in a large panel of lymphoid tumors, including acute and chronic lymphoid leukemias (96 cases), various NHL types (125 cases), and multiple myelomas (23 cases). BCL6 rearrangements were found in 16/45 (35.5%) DLLC, more frequently in DLCL (15/33, 45%) than in MX-D (1/10, 10%), in 2/31 (6.4%) follicular NHL, and in no other tumor types. BCL6 rearrangements represent the first genetic lesion specifically and recurrently associated with DLLC and should prove useful for understanding the pathogenesis as well as for the clinical monitoring of these tumors.

DNA-Binding Proteins↗
PubMed1994

Molecular genetic demonstration of the diverse evolution of Richter's syndrome (chronic lymphocytic leukemia and subsequent large cell lymphoma).

Paired samples of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and the subsequent diffuse large cell lymphoma (DLL) of six cases of Richter's syndrome were investigated to establish the clonal relationship between the CLL/SLL and the DLL components and to define the oncogene and/or tumor-suppressor gene alterations involved in the morphologic transformation of CLL/SLL. Southern blot hybridization analysis showed identical clonal immunoglobulin (Ig) gene-rearrangement patterns in the CLL/SLL and DLL components in four cases and different Ig gene-rearrangement patterns in two cases. Polymerase chain reaction (PCR) amplification, cloning, and DNA sequencing of complementary determinant region 3 (CDR3) of the Ig-heavy chain gene of one of the two cases in which the Ig gene-rearrangement patterns were different showed nonidentical sequences in the CLL/SLL and DLL components. In the other case, monomorphic Epstein-Barr virus (EBV) genome integration was detected in the DLL but not in the CLL, suggesting that the CLL and DLL components in this case of Richter's syndrome also represent unrelated clones. Single-strand conformation polymorphism (SSCP) analysis and sequencing of exons 5 through 9 of the p53 tumor-suppressor gene showed a mutation in codon 176 of the DLL but not in the CLL/SLL component in one case where the CLL/SLL and DLL represented different clones. The p53 mutation probably played a role in the development of the lymphoma rather than morphologic transformation of the CLL/SLL in this case. SSCP analysis and sequencing also showed identical mutations in codon 282 in both the CLL/SLL and DLL components in a case where the CLL and DLL represented identical clones. Thus, this p53 gene mutation was present both before and after morphologic transformation, and therefore, probably did not play a primary role in this process. Southern blot hybridization analysis failed to show evidence of bcl-1, bcl-2, c-myc proto-oncogene or retinoblastoma (Rb) tumor-suppressor gene rearrangements in these six cases of Richter's syndrome. In conclusion, the original CLL/SLL and the subsequent DLL in Richter's syndrome may or may not be derived from identical clones, and the well-known proto-oncogenes and tumor-suppressor genes do not appear to play an obvious and consistent role in the morphologic transformation of CLL/SLL to DLL.

Adult↗
PubMed1994

Paraffin-resistant antigens detectable by antibodies L26 and polyclonal CD3 predict the B- or T-cell lineage of 95% of diffuse aggressive non-Hodgkin's lymphomas.

The reactivity of eight preferential B-cell (L26, 4KB5, and KiB3) and T-cell (polyclonal CD3, Leu22, MT-1, UCHL-1, and OPD4) antibodies which detect paraffin-resistant antigens was examined by a three-step immunoperoxidase technique in 111 formalin-fixed, paraffin-embedded diffuse aggressive non-Hodgkin's lymphomas (NHLs) to determine the optimal panel for accurate lineage assignment. L26 (CD20) and polyclonal CD3 (CD3) were the most sensitive (> 95%) and specific (100%) antibodies. They identified the B- or T-cell lineages correctly in 106 (95%) cases. The five L26-negative, polyclonal CD3-negative cases included all three precursor B lymphoblastic NHLs and two (one B and one T) diffuse large-cell NHLs. Immunostaining with the second most sensitive preferential B-cell (4KB5) and T-cell (Leu22) antibodies correctly identified the lineage in two additional NHLs, but one false-positive result occurred. Preferential B-cell antibody KiB3 reacted with two precursor B lymphoblastic NHLs. Use of additional paraffin-reactive antibodies did not increase the number of NHLs assigned to the correct cell lineage. In conclusion, it appears that a two-tiered approach, with a first-line panel consisting of L26 and polyclonal CD3, followed by 4KB5 and Leu22 in nonlymphoblastic NHLs and by KiB3 in lymphoblastic NHLs, represents the most efficient method of correctly identifying the B- or T-cell lineage of diffuse aggressive NHLs by paraffin tissue section immunohistochemistry.

Antibodies, Monoclonal↗
PubMed1994

Identification of genetic lesions associated with diffuse large-cell lymphoma.

BACKGROUND: The pathogenesis of several subtypes of non-Hodgkin's lymphoma (NHL) is associated with specific genetic lesions involving oncogenes and tumor-suppressor genes. These lesions include c-myc translocation and p53 inactivation in small noncleaved-cell lymphoma, and bcl-2 and bcl-1 translocation in follicular (FL) and mantle-zone lymphoma, respectively. Relatively little is known, however, about the pathogenesis of diffuse lymphoma with a large-cell component (DLLC; including large-, mixed-cell, and immunoblastic), the most relevant NHL type in terms of morbidity and mortality. Since DLLC can occur 'de novo' or via histologic transformation of follicular lymphoma, it is critical to identify lesions associated with both pathogenetic pathways. DESIGN: The present work is aimed at (i) identifying the role of cytogenetic and molecular lesions involving oncogenes or tumor-suppressor genes in the transformation of FL into DLLC in a series of 5 patients for whom sequential biopsies were available pre- and post-transformation and (ii) identifying novel proto-oncogenes involved in DLLC pathogenesis by molecular analysis of chromosomal translocations affecting band 3q27, which are common in DLLC. RESULTS: Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL. A novel proto-oncogene, bcl-6, coding for a zinc-finger transcription factor, was cloned from 3q27 breakpoints and shown to be structurally altered in 33% (13/39) of DLLC samples studied, but not in other types of lymphoid malignancies. CONCLUSIONS: These results indicate that inactivation of the p53 tumor-suppressor gene may complement bcl-2 activation and be involved in the transformation of FL into DLLC. Activation of the bcl-6 oncogene may represent one of the steps in the pathogenesis of 'de novo' DLLC. Both lesions should prove useful as diagnostic and prognostic markers in the clinical management of these tumors.

Humans↗
PubMed1994

Alterations of the beta-adrenergic receptor system after thoracic and abdominal surgery.

We studied perioperative regulation of the beta-adrenergic receptor (beta AR) in lymphocytes obtained from 12 patients undergoing noncardiac thoracic surgery and 12 patients undergoing abdominal surgery. beta AR number (Bmax) and dissociation constant (KD) were determined from [125I]iodopindolol saturation binding curves. Function of the beta AR/adenylyl cyclase system was assessed by measuring cyclic adenosine monophosphate (cAMP) production in the unstimulated state and in response to maximal stimulation by isoproterenol (ISO) and prostaglandin E1 (PGE1). In thoracic surgery patients, basal and ISO-stimulated cAMP production were significantly decreased postoperatively, by 44% and 45%, respectively, with no change in PGE1-stimulated cAMP. Bmax decreased from 1369 +/- 138 (mean +/- SE) sites/cell to 891 +/- 82 sites/cell postoperatively, while the KD increased from 26.7 +/- 5.6 pM to 37.8 +/- 5.1 pM. In the abdominal surgery patients, there were no significant alterations in cAMP production, but Bmax decreased, from 1235 +/- 146 sites/cell preoperatively to 888 +/- 65 sites/cell postoperatively, while the KD increased from 18.8 +/- 3.6 pM to 58.1 +/- 12.5 pM. The beta AR and its associated effector system are altered during the perioperative period of abdominal and thoracic surgery.

Abdomen↗
PubMed1994

Post-thymic T cell lymphomas frequently overexpress p53 protein but infrequently exhibit p53 gene mutations.

We recently demonstrated that only one of 36 T-cell neoplasms contained p53 gene mutations. Although p53 gene mutations are known to result in overexpression of the p53 gene product, we also recently discovered that p53 protein overexpression does not correlate with p53 gene mutations, but does correlate with proliferation (r = 0.92), in anaplastic large cell lymphoma. In view of these findings, we investigated 34 non-human T-cell lymphotropic virus type I (HTLV-I) related postthymic T-cell lymphomas immunohistochemically for p53 protein, using monoclonal antibody 1801, and for proliferation, using monoclonal antibody Ki-67, and quantitated the results with the CAS-200 computerized image analysis system. We evaluated the presence of mutations in conserved exons 5 to 9 of the p53 gene using single-strand conformation polymorphism analysis and DNA sequencing. p53 mutations were detected in three of 34 cases, including two that contained deletions. p53 protein overexpression was detected in 17 of 34 cases, including the three mutated cases, with reactivities ranging from 10% to 48%. However, many cases in which a structural alteration could not be detected demonstrated levels of p53 protein expression comparable to those cases that were mutated. Correlation of p53 protein expression and proliferation, as assessed by Ki-67 expression, in this group of lymphomas was poor (r = 0.34). Whether alternative mechanisms of p53 protein inactivation are causing phenotypic overexpression of the p53 protein in these malignant lymphomas is unknown, although preliminary studies do not support a major role for such mechanisms. Therefore, the etiology and the significance of p53 protein overexpression in the cases that lack a demonstrable mutation is unclear. Nevertheless, as in anaplastic large cell lymphoma, overexpression of the p53 gene product is not a reliable predictor of the presence of mutations in conserved portions of the p53 gene in non-HTLV-I associated post-thymic T-cell lymphoma.

Antibodies, Monoclonal↗
PubMed1994

Inactivation of tumor suppressor genes, p53 and Rb1, in plasma cell dyscrasias.

The role of loss or inactivation of the retinoblastoma (Rb1) and p53 tumor suppressor genes in the pathogenesis of various human malignancies has been well established, yet little is known regarding plasma cell dyscrasias. In the present study, the loss of Rb1 protein expression, and the presence of Rb1 gene rearrangements as well as the presence of p53 somatic mutations (exons 5 through 9) were investigated in a panel of plasma cell dyscrasias, including 15 monoclonal gammopathies of undetermined significance (MGUS), 63 multiple myelomas (MM), and 18 plasma cell leukemias (PCL). In the same panel of cases, we established the frequency of ras oncogene mutations, the main genetic lesion associated with MM. We report that loss of Rb1 protein and p53 mutations are detectable in 34.7 and 9.8% of MM and PCL primary cases; no lesion was found in MGUS. In advanced stage MM, and PCL cases, Rb1 and p53 inactivation, as well as ras mutations were detected. Our findings show that Rb1 and p53 inactivation are associated with aggressive plasma cell dyscrasias, suggesting a role for these lesions in tumor progression rather than initiation.

Base Sequence↗
PubMed1993

CD30 (Ki-1) positive anaplastic large cell lymphomas in individuals infected with the human immunodeficiency virus.

BACKGROUND: CD30 (Ki-1) positive anaplastic large cell lymphoma (ALCL) has been only rarely described in HIV-positive patients. METHODS: The clinicopathologic features of eight ALCLs occurring in four AIDS and four HIV-positive patients were investigated. The phenotype of each neoplasm was determined by immunohistochemical methods. In three cases fresh tissue was available for molecular analysis. RESULTS: The ALCLs are a clinically heterogeneous group of T (4), B (1) and indeterminate (3) cell malignant lymphomas which presented in the skin (4), liver (1), lung (1), nasal cavity (1; also with bone marrow involvement) and peritoneal fluid (1). While most of the patients had aggressive disease, dying in a median of three months, two patients had either localized or regressing skin lesions. Molecular studies showed that two ALCLs, one of B cell and one of indeterminate cell lineage, contained clonal Epstein-Barr virus sequences. None of the ALCLs examined contained evidence of HTLV-1 or HIV integration nor did they exhibit c-myc or bcl-2 proto-oncogene rearrangements. No mutations or deletions of the p53 tumor suppressor gene were identified in the three cases studied. CONCLUSIONS: HIV-related ALCL represents a clinically heterogeneous group of T cell, B cell and null cell malignant lymphomas, distinct from the previously described categories of AIDS-associated NHL, that may expand the spectrum of lymphoid neoplasms associated with HIV-infection. Identification and investigation of other cases of HIV-associated ALCL is important to determine the nature of the relationship between HIV infection and the development of ALCL.

Adult↗