Asunto(s)

Linfoma , Humanos , Linfoma/terapia , Suiza , Congresos como Asunto

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Leucemia de Células Pilosas/genética , Sistema de Señalización de MAP Quinasas , MicroARNs/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Estudios de Casos y Controles , Humanos , Leucemia de Células Pilosas/sangre , MicroARNs/metabolismo

RESUMEN

To characterize the molecular origin of primary lymphomas of the central nervous system (PCNSL), 21 PCNSLs of immunocompetent patients were investigated by microarray-based gene expression profiling. Comparison of the transcriptional profile of PCNSL with various normal and neoplastic B-cell subsets demonstrated PCNSL (i) to display gene expression patterns most closely related to late germinal center B cells, (ii) to display a gene expression profile similar to systemic diffuse large B-cell lymphomas (DLBCLs) and (iii) to be in part assigned to the activated B-cell-like (ABC) or the germinal center B-cell-like (GCB) subtype of DLBCL.

Asunto(s)

Linfocitos B/patología , Neoplasias del Sistema Nervioso Central/genética , Perfilación de la Expresión Génica , Centro Germinal/patología , Linfoma/genética , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Inmunocompetencia , Linfoma/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Análisis por Micromatrices , Persona de Mediana Edad

RESUMEN

For many decades, B cell chronic lymphocytic leukemia (B-CLL) stood out as a B cell-derived malignancy that was difficult to position within the framework of the available B cell differentiation scheme: First, the histology as well as the immunophenotype did not quite resemble that of any normal lymphocyte; second, in contrast to almost all other B cell tumor subtypes, the immunoglobulin variable region (IgV) genes of B-CLL cases could be either unmutated or somatically mutated; third, the genomic lesions observed in B-CLL were markedly distinct from those of the other major B cell malignancies, which typically exhibit balanced chromosome translocations. Recent advances in the characterization of both B-CLL and normal B cell subpopulations by phenotypic analysis, global gene expression profiling, as well as extensive IgV gene repertoire analyses have shed new light on the phenotype and the cell derivation of B-CLL and provided novel hypotheses concerning its pathogenesis. Here we summarize recent work relevant to these issues and conclude that B-CLL may be derived from a cell that can be referred to as a marginal zone B cell. Moreover, we propose that the lack of chromosomal translocations in B-CLL may be related to their derivation from marginal zone B cells, since somatic hypermutation and Ig class switch, the processes that generate chromosome translocations in most germinal center (GC)-derived malignancies, are no longer active in marginal zone B cells. Also, we discuss similarities and differences between B-CLL and hairy cell leukemia (HCL) and suggest that also HCL may be derived from a post-GC memory or marginal zone B cell.

Asunto(s)

Leucemia Linfocítica Crónica de Células B/etiología , Animales , Perfilación de la Expresión Génica , Humanos , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/clasificación , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Ratones , Modelos Biológicos , Mutación , Fenotipo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo

RESUMEN

Immunoglobulin-like transcript 3 (ILT3) and ILT4 belong to a family of inhibitory receptors expressed by human monocytes and dendritic cells. We show here that CD8+CD28(-) alloantigen-specific T suppressor (TS) cells induce the up-regulation of ILT3 and ILT4 on monocytes and dendritic cells, rendering these antigen-presenting cells (APCs) tolerogenic. Tolerogenic APCs show reduced expression of costimulatory molecules and induce antigen-specific unresponsiveness in CD4+ T helper cells. Studies of human heart transplant recipients showed that rejection-free patients have circulating TS cells, which induce the up-regulation of ILT3 and ILT4 in donor APCs. These findings demonstrate an important mechanism of immune regulation.

Asunto(s)

Células Dendríticas/fisiología , Tolerancia Inmunológica , Receptores de Superficie Celular/fisiología , Receptores Inmunológicos/fisiología , Linfocitos T Reguladores/inmunología , Células Presentadoras de Antígenos/química , Células Presentadoras de Antígenos/fisiología , Antígenos CD28/análisis , Antígenos CD8/análisis , Humanos , Glicoproteínas de Membrana , FN-kappa B/fisiología

RESUMEN

B cell-derived chronic lymphocytic leukemia (B-CLL) represents a common malignancy whose cell derivation and pathogenesis are unknown. Recent studies have shown that >50% of CLLs display hypermutated immunoglobulin variable region (IgV) sequences and a more favorable prognosis, suggesting that they may represent a distinct subset of CLLs which have transited through germinal centers (GCs), the physiologic site of IgV hypermutation. To further investigate the phenotype of CLLs, their cellular derivation and their relationship to normal B cells, we have analyzed their gene expression profiles using oligonucleotide-based DNA chip microarrays representative of approximately 12,000 genes. The results show that CLLs display a common and characteristic gene expression profile that is largely independent of their IgV genotype. Nevertheless, a restricted number of genes (<30) have been identified whose differential expression can distinguish IgV mutated versus unmutated cases and identify them in independent panels of cases. Comparison of CLL profiles with those of purified normal B cell subpopulations indicates that the common CLL profile is more related to memory B cells than to those derived from naive B cells, CD5(+) B cells, and GC centroblasts and centrocytes. Finally, this analysis has identified a subset of genes specifically expressed by CLL cells of potential pathogenetic and clinical relevance.

Asunto(s)

Linfocitos B/inmunología , Expresión Génica , Memoria Inmunológica/inmunología , Leucemia Linfocítica Crónica de Células B/genética , Perfilación de la Expresión Génica , Humanos , Región Variable de Inmunoglobulina/genética , Inmunofenotipificación , Mutación

RESUMEN

Dendritic cells are crucial to the activation as well as suppression of the immune response. Previous reports have illustrated that APC interacting with antigen-specific T suppressor cells become tolerogenic, inducing T helper anergy. To characterize the molecular changes occurring in tolerogenic APC, the mRNA profile of KG-1 dendritic cells exposed to allospecific T helper and T suppressor cells were analyzed. This study now provides evidence that immature dendritic cells stimulated by T suppressor cells differentiate into mature dendritic cells with a distinct phenotype. The identification of Ts induced pathways of dendritic cell differentiation is critical to the development of new therapeutic strategies.

Asunto(s)

Células Dendríticas/inmunología , Perfilación de la Expresión Génica , Tolerancia Inmunológica , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Antígenos de Diferenciación , Apoptosis/genética , Apoptosis/inmunología , Comunicación Celular/genética , Comunicación Celular/inmunología , Proteínas de Ciclo Celular , División Celular/genética , División Celular/inmunología , Línea Celular , Quimiocinas/biosíntesis , Quimiocinas/genética , Quimiocinas/metabolismo , Técnicas de Cocultivo , Ciclooxigenasa 2 , Citocinas/biosíntesis , Citocinas/genética , Células Dendríticas/citología , Células Dendríticas/enzimología , Células Dendríticas/metabolismo , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Perfilación de la Expresión Génica/métodos , Humanos , Tolerancia Inmunológica/genética , Isoenzimas/biosíntesis , Isoenzimas/genética , Activación de Linfocitos/genética , Proteínas de la Membrana , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Prostaglandina-Endoperóxido Sintasas/genética , Biosíntesis de Proteínas , Proteína Fosfatasa 1 , Proteínas/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Células Tumorales Cultivadas , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología

RESUMEN

Reciprocal chromosomal translocations involving the immunoglobulin (Ig) loci are a hallmark of most mature B cell lymphomas and usually result in dysregulated expression of oncogenes brought under the control of the Ig enhancers. Although the precise mechanisms involved in the development of these translocations remains essentially unknown, a clear relationship has been established with the mechanisms that lead to Ig gene remodeling, including V(D)J recombination, isotype switching and somatic hypermutation. The common denominator of these three processes in the formation of Ig-associated translocations is probably represented by the fact that each of these processes intrinsically generates double-strand DNA breaks. Since isotype switching and somatic hypermutation occur in germinal center (GC) B cells, the origin of a large number of B cell lymphomas from GC B cells is likely closely related to aberrant hypermutation and isotype switching activity in these B cells.

Asunto(s)

Linfoma de Células B/genética , Modelos Genéticos , Translocación Genética , Alelos , Animales , ADN Nucleotidiltransferasas/metabolismo , Humanos , Inmunoglobulinas/genética , Linfoma de Células B Grandes Difuso/genética , Ratones , Mutación , Recombinación Genética , VDJ Recombinasas

RESUMEN

Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells. Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1, MYC, RhoH/TTF (ARHH) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.

Asunto(s)

Linfocitos B , Proteínas de Unión al ADN , Linfoma de Células B/genética , Linfoma de Células B Grandes Difuso/genética , Mutación , Proto-Oncogenes , Factores de Transcripción , Análisis Mutacional de ADN , Genes myc , Centro Germinal/citología , Humanos , Linfoma de Células B/inmunología , Linfoma de Células B Grandes Difuso/inmunología , Datos de Secuencia Molecular , Factor de Transcripción PAX5 , Proteínas/genética

RESUMEN

Abnormalities of chromosome 1q21 are common in B cell malignancies, but their target genes are largely unknown. By cloning the breakpoints of a (1;14) (q21;q32) chromosomal translocation in a myeloma cell line, we have identified two novel genes, IRTA1 and IRTA2, encoding cell surface receptors homologous to the Fc and inhibitory receptor families. Both genes are selectively expressed in mature B cells: IRTA1 in marginal zone B cells and IRTA2 in centrocytes, marginal zone B cells, and immunoblasts. As a result of the t(1;14), IRTA1 is fused to the immunoglobulin Calpha domain to produce a chimeric IRTA1/Calpha fusion protein. In tumor cell lines with 1q21 abnormalities, IRTA2 expression is deregulated. Thus, IRTA1 and IRTA2 are novel immunoreceptors implicated in B cell development and lymphomagenesis.

Asunto(s)

Linfocitos B/metabolismo , Cromosomas Humanos Par 1/genética , Inmunoglobulinas/química , Linfoma de Células B/genética , Receptores de Superficie Celular/metabolismo , Translocación Genética/genética , Secuencia de Aminoácidos , Linfocitos B/química , Linfocitos B/citología , Linfocitos B/patología , Secuencia de Bases , Rotura Cromosómica/genética , Cromosomas Humanos Par 14/genética , Clonación Molecular , Exones/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Mutación de Línea Germinal/genética , Humanos , Intrones/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Datos de Secuencia Molecular , Familia de Multigenes/genética , Proteínas de Mieloma/química , Proteínas de Mieloma/genética , Proteínas de Mieloma/metabolismo , Proteínas de Fusión Oncogénica/química , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Estructura Terciaria de Proteína , ARN Mensajero/análisis , ARN Mensajero/genética , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Receptores Fc/química , Células Tumorales Cultivadas

RESUMEN

Deletions of the 13q14 chromosome region are associated with B-cell chronic lymphocytic leukemia (B-CLL) and several other types of cancer, suggesting the presence of a tumor suppressor gene. In previous studies the minimal region of deletion (MDR) was mapped to a less than 300-kilobase (kb) interval bordered by the markers 173a12-82 and 138G4/1.3R. For the identification of the putative tumor suppressor gene, the entire MDR (approximately 347 kb) has been sequenced, and transcribed regions have been identified by exon trapping, EST-based full-length complementary DNA cloning, database homology searches, and computer-assisted gene prediction analyses. The MDR contains 2 pseudogenes and 3 transcribed genes: CAR, encoding a putative RING-finger containing protein; 1B4/Leu2, generating noncoding transcripts; and EST70/Leu1, probably representing another noncoding gene (longest open reading frame of 78 codons). These genes have been sequenced in 20 B-CLL cases with 13q14 hemizygous deletion, and no mutations were found. Moreover, no somatic variants were found in the entire MDR analyzed for nucleotide substitutions by a combination of direct sequencing and fluorescence-assisted mismatch analysis in 5 B-CLL cases displaying 13q14-monoallelic deletion. The nondeleted allele of the CAR and EST70/Leu1 genes was expressed in B-CLL specimens, including those with monoallelic loss, whereas no expression of 1B4/Leu2 was detectable in B-CLL, regardless of the 13q14 status. These results indicate that allelic loss and mutation of a gene within the MDR is an unlikely pathogenetic mechanism for B-CLL. However, haplo-insufficiency of one of the identified genes may contribute to tumorigenesis. (Blood. 2001;97:2098-2104)

Asunto(s)

Cromosomas Humanos Par 13/genética , ADN de Neoplasias/genética , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Animales , Secuencia de Bases , Transformación Celular Neoplásica/genética , Mapeo Cromosómico , Cromosomas Humanos Par 13/ultraestructura , Análisis Mutacional de ADN , ADN Complementario/genética , Etiquetas de Secuencia Expresada , Genes Supresores de Tumor , Humanos , Ratones , Datos de Secuencia Molecular , Proteínas/genética , Seudogenes , ARN Largo no Codificante , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Eliminación de Secuencia , Transcripción Genética , Transferasas , Proteínas Supresoras de Tumor

RESUMEN

This study was aimed at defining the histogenesis of the pathologic spectrum of lymphoma arising in the context of human immunodeficiency virus (HIV) infection. Toward this aim, 87 AIDS-related non-Hodgkin lymphomas (AIDS-NHL) and 16 Hodgkin lymphomas arising in HIV+ patients (HIV-HL) were comparatively analyzed for the expression pattern of several B-cell histogenetic markers, including BCL-6 (expressed by centroblasts and centrocytes), MUM1/IRF4 (expressed by late centrocytes and post-germinal center [GC] B cells), and CD138/syn-1 (expressed by post-GC B cells). Expression of MUM1, BCL-6, and syn-1 segregated 3 major phenotypic patterns among AIDS-NHL and HIV-HL: (1) the BCL-6+/MUM1-/syn-1- pattern, selectively clustering with a large fraction of AIDS-Burkitt lymphoma (17 of 19) and of systemic AIDS-diffuse large cell lymphoma (12 of 16); (2) the BCL-6-/MUM1+/syn-1- pattern, associated with a fraction of AIDS-immunoblastic lymphoma (8 of 24); and (3) the BCL-6-/MUM1+/syn-1+ pattern, associated with systemic and primary central nervous system immunoblastic lymphoma (14 of 24) and with primary effusion lymphoma (10 of 10), plasmablastic lymphoma of the oral cavity (7 of 7), and HIV-HL (15 of 16). Analysis of nonneoplastic lymph nodes showed that the 3 phenotypic patterns detected in AIDS-NHL and HIV-HL correspond to distinct stages of physiologic B-cell development-centroblasts (BCL-6+/MUM1-/syn-1-), late GC/early post-GC B cells (BCL-6-/MUM1+/syn-1-), and post-GC B cells (BCL-6-/MUM1+/syn-1+). Expression of the Epstein-Barr virus-encoded latent membrane protein-1 clustered with the BCL-6-/MUM1+/syn-1+ profile throughout the clinicopathologic spectrum of AIDS-NHL and HIV-HL. Overall, these results define novel histogenetic subsets of AIDS-NHL and HIV-HL and may provide novel tools for refining the diagnosis of these disorders.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Proteínas de Unión al ADN/metabolismo , Linfoma Relacionado con SIDA/clasificación , Glicoproteínas de Membrana/metabolismo , Proteoglicanos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/metabolismo , Linfocitos B/inmunología , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/virología , Expresión Génica , Herpesvirus Humano 4/aislamiento & purificación , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/virología , Humanos , Factores Reguladores del Interferón , Ganglios Linfáticos/inmunología , Linfoma Relacionado con SIDA/metabolismo , Linfoma Relacionado con SIDA/virología , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/virología , Modelos Biológicos , Tonsila Palatina/inmunología , Fenotipo , Proteínas Proto-Oncogénicas c-bcl-6 , Sindecano-1 , Sindecanos

Asunto(s)

Deleción Cromosómica , Cromosomas Humanos Par 13/ultraestructura , Genes Supresores de Tumor , Leucemia Linfocítica Crónica de Células B/genética , Alelos , Antígenos de Neoplasias/análisis , Antígenos CD5/análisis , Línea Celular Transformada , Mapeo Cromosómico , Cromosomas Humanos Par 13/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Mutación , Proteínas de Neoplasias/genética , Proto-Oncogenes

RESUMEN

The cell of origin of B-cell chronic lymphocytic leukemia (B-CLL) is still uncertain. Recent studies have indicated that a fraction of B-CLL displays somatically mutated immunoglobulin variable heavy chain (IgV(H)) genes, which suggests an origin from a post-germinal center (GC) B cell. It has been shown that the 5' noncoding region of the BCL-6 proto-oncogene is affected by mutations in normal GC B-lymphocytes and in lymphoid malignancies displaying GC/post-GC phenotype. To further explore the cellular origin of B-CLL, we have analyzed 34 cases for mutations in the BCL-6 5' noncoding region and in the IgV(H) genes. We found somatically mutated IgV(H) genes in 24 (73%) of 33 samples (average frequency, 6.5 x 10(-2)/bp) and BCL-6 mutations in 8 (24%) of 34 cases (average frequency, 0.14 x 10(-2)/bp in the mutated cases). The occurrence of BCL-6 mutations was restricted to those cases displaying IgV(H) mutations. Analysis of BCL-6 protein expression as a marker of GC phenotype showed that, regardless of the presence of IgV(H) or BCL-6 mutations, B-CLLs express BCL-6 at levels clearly below those found in normal or transformed GC B cells. These results indicate that a subset of B-CLL derives from a cell that has been exposed to the somatic hypermutation mechanism and support the hypothesis that BCL-6 mutations result from the same process that targets immunoglobulin genes.

Asunto(s)

Proteínas de Unión al ADN/genética , Genes de Inmunoglobulinas/genética , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Proteínas de Unión al ADN/biosíntesis , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-6 , Factores de Transcripción/biosíntesis

RESUMEN

A region of minimal deletion in B-cell non-Hodgkin's lymphoma (B-NHL) has recently been defined between D6S186 and D6S227 spanning 5-9 Mb at 6q26-q27, predicting the presence of at least one tumor suppressor gene (TSG) at this locus. During the construction of a deletion map in the B-NHL tumor panel, we report the identification of a Burkitt's lymphoma cell line, BL74, having an apparent homozygous deletion at the D6S347 locus, internal to the critical region. Since this case may facilitate the localization of the target TSG, a detailed structural molecular characterization and search for candidate genes were undertaken at this locus. While BL74 underwent a loss of heterozygosity at 6q26-q27, D6S347 was also likely subjected to a somatic interlocus gene conversion-like event between two homologous but distinct loci, resulting in the homozygous replacement of a 1860- to 2067-bp segment of one locus with the corresponding segment copied from the other locus. Two genes at this locus were identified, but their lack of expression in B-cell lineages tentatively excludes them as candidate TSGs. Another still unidentified gene at this locus may be disrupted by the gene conversion-like event, which would represent a novel mechanism of TSG inactivation.

Asunto(s)

Linfoma de Burkitt/genética , Cromosomas Humanos Par 6/genética , Genes Supresores de Tumor/genética , Alelos , Secuencia de Bases , Northern Blotting , Southern Blotting , Mapeo Cromosómico , Electroforesis en Gel de Campo Pulsado , Exones , Conversión Génica , Eliminación de Gen , Humanos , Pérdida de Heterocigocidad , Modelos Genéticos , Datos de Secuencia Molecular , Polimorfismo de Longitud del Fragmento de Restricción , ARN/metabolismo , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico , Transcripción Genética , Células Tumorales Cultivadas

RESUMEN

A new monoclonal antibody (MUM1p) was used to study the cell/tissue expression of human MUM1/IRF4 protein, the product of the homologous gene involved in the myeloma-associated t(6;14) (p25;q32). MUM1 was expressed in the nuclei and cytoplasm of plasma cells and a small percentage of germinal center (GC) B cells mainly located in the "light zone." Its morphologic spectrum ranged from that of centrocyte to that of a plasmablast/plasma cell, and it displayed a phenotype (MUM1(+)/Bcl-6(-)/Ki67(-)) different from that of most GC B cells (MUM1(-)/Bcl-6(+)/Ki67(+)) and mantle B cells (MUM1(-)/Bcl-6(-)/Ki67(-)). Polymerase chain reaction (PCR) analysis of single MUM1(+ )cells isolated from GCs showed that they contained rearranged Ig heavy chain genes with a varying number of V(H) somatic mutations. These findings suggest that these cells may represent surviving centrocytes and their progeny committed to exit GC and to differentiate into plasma cells. MUM1 was strongly expressed in lymphoplasmacytoid lymphoma, multiple myeloma, and approximately 75% of diffuse large B-cell lymphomas (DLCL-B). Unlike normal GC B cells, in which the expression of MUM1 and Bcl-6 were mutually exclusive, tumor cells in approximately 50% of MUM1(+) DLCL-B coexpressed MUM1 and Bcl-6, suggesting that expression of these proteins may be deregulated. In keeping with their proposed origin from GC B cells, Hodgkin and Reed-Sternberg cells of Hodgkin's disease consistently expressed MUM1. MUM1 was detected in normal and neoplastic activated T cells, and its expression usually paralleled that of CD30. These results suggest that MUM1 is involved in the late stages of B-cell differentiation and in T-cell activation and is deregulated in DLCL-B. (Blood. 2000;95:2084-2092)

Asunto(s)

Anticuerpos Monoclonales , Linfocitos B/metabolismo , Proteínas de Unión al ADN/metabolismo , Células Plasmáticas/metabolismo , Linfocitos T/metabolismo , Factores de Transcripción/metabolismo , Linfocitos B/inmunología , Biomarcadores de Tumor/metabolismo , Western Blotting , Línea Celular , Homólogo de la Proteína Chromobox 5 , Epítopos , Células HeLa , Humanos , Región Variable de Inmunoglobulina/metabolismo , Inmunohistoquímica , Factores Reguladores del Interferón , Células Jurkat , Ganglios Linfáticos/metabolismo , Linfoma/metabolismo , Mieloma Múltiple/metabolismo , Células Plasmáticas/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Linfocitos T/inmunología , Factores de Tiempo , Transfección

RESUMEN

BCL-6 mutations are accumulated during B-cell transit through the germinal center (GC) and provide a histogenetic marker for B-cell tumors. On the basis of a comprehensive analysis of 308 B-cell neoplasms, we (1) expand the spectrum of tumors associated with BCL-6 mutations; (2) corroborate the notion that mutations cluster with GC and post-GC B-cell neoplasms; and (3) identify heterogeneous mutation frequency among B-lineage diffuse large cell lymphoma (B-DLCL) subsets. Mutations are virtually absent in acute lymphoblastic leukemia (P <.001) and mantle cell lymphoma (P <.05), whereas they occur frequently in GC or post-GC neoplasms, including lymphoplasmacytoid lymphoma, follicular lymphoma, MALT lymphomas, B-DLCL and Burkitt lymphoma. Among B-DLCL, mutations occur frequently in systemic nodal B-DLCL, primary extranodal B-DLCL, CD5(+) B-DLCL, CD30(+) B-DLCL, and primary splenic B-DLCL, suggesting a similar histogenesis of these B-DLCL subsets. Conversely, mutations are rare in primary mediastinal B-DLCL with sclerosis (10.0%; P <.01), supporting a distinct histogenesis for this lymphoma. Longitudinal follow-up of B-DLCL transformed from follicular lymphoma shows that they BCL-6 mutations may accumulate during histologic progression. Mutations also occur in some B-cell chronic lymphocytic leukemias, small lymphocytic lymphomas, and hairy cell leukemias, consistent with the hypothesis that a fraction of these lymphoproliferations are related to GC-like cells. Finally, the molecular pattern of 193 mutational events reinforces the hypothesis that mutations of BCL-6 and immunoglobulin genes are caused by similar mechanisms. (Blood. 2000;95:651-659)

Asunto(s)

Proteínas de Unión al ADN/genética , Leucemia de Células B/genética , Linfoma de Células B/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes , Factores de Transcripción/genética , Secuencia de Bases , Humanos , Leucemia de Células B/mortalidad , Leucemia de Células B/patología , Linfoma de Células B/mortalidad , Linfoma de Células B/patología , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Proteínas Proto-Oncogénicas c-bcl-6 , Tasa de Supervivencia

RESUMEN

The transcriptional repressor protein BCL-6, implicated in the pathogenesis of B cell lymphoma, regulates lymphocyte differentiation and inflammation. We investigated the mechanism for the T helper cell subset 2 (TH2)-type inflammation that occurs in BCL-6-/- mice. Using chimeric mice we found that the TH2-type inflammation is dependent upon nonlymphoid cells. We identified three chemokines, MCP-1, MCP-3 and MRP-1, which are negatively regulated by BCL-6 in macrophages. Promoter analysis revealed that BCL-6 is a potent repressor of MCP-1 transcription. Our results provide a mechanism for the regulation of TH2-type inflammation by BCL-6 and link TH2 differentiation to innate immunity.

Asunto(s)

Quimiocinas CC , Quimiocinas/genética , Citocinas , Proteínas de Unión al ADN/fisiología , Regulación de la Expresión Génica/fisiología , Macrófagos/fisiología , Proteínas Proto-Oncogénicas/fisiología , Factores de Transcripción/fisiología , Transcripción Genética/fisiología , Animales , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL7 , Quimiocinas/biosíntesis , Quimiocinas/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Centro Germinal/citología , Centro Germinal/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Quimioatrayentes de Monocitos/biosíntesis , Proteínas Quimioatrayentes de Monocitos/genética , Proteínas Quimioatrayentes de Monocitos/inmunología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/inmunología , Proteínas Proto-Oncogénicas c-bcl-6 , Células Th2/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología

RESUMEN

Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) consistently derive from B cells, are histologically heterogeneous, and are associated with distinct molecular pathways depending upon histology. Recently, it has been proposed that inactivating mutations of the bax death agonist may contribute to the pathogenesis of human tumors. In particular, among B-cell malignancies, BAX mutations have been detected at a certain frequency in Burkitt lymphomas. This study is aimed at defining the status of the BAX gene throughout the clinicopathologic spectrum of AIDS-NHL (n = 54), including AIDS-related Burkitt lymphoma (n = 14), AIDS-related Burkitt-like lymphoma (n = 8), AIDS-related diffuse large cell lymphoma (n = 15), AIDS-related primary central nervous system lymphoma (n = 6), and AIDS-related primary effusion lymphoma (n = 11). All 6 BAX exons and flanking sequences were subjected to mutational analysis by polymerase chain reaction-single strand conformation polymorphism followed by DNA direct sequencing of positive cases. Mutations of BAX among AIDS-NHL were restricted to a cell line of AIDS-related primary effusion lymphoma, which harbored a frameshift mutation causing the introduction of a proximal stop codon. All other AIDS-NHL displayed wild-type BAX alleles. In order to investigate whether BAX inactivation in AIDS-NHL may occur through mechanisms other than gene mutation, bax protein expression was investigated by Western blot analysis or immunohistochemistry in selected cases. All AIDS-NHL analyzed expressed normal bax proteins. Overall, this study indicates that deregulation of apoptotic control in AIDS-NHL is not caused by BAX alterations. Genes Chromosomes Cancer 27:177-182, 2000.

Asunto(s)

Linfoma Relacionado con SIDA/genética , Linfoma no Hodgkin/genética , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas/genética , Western Blotting , Análisis Mutacional de ADN , ADN de Neoplasias/química , ADN de Neoplasias/genética , Humanos , Mutación , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Proteínas Proto-Oncogénicas/metabolismo , Eliminación de Secuencia , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Proteína X Asociada a bcl-2

RESUMEN

The BCL-6 proto-oncogene encodes a POZ/zinc-finger transcription factor that is expressed in B cells and a subset of CD4(+) T cells within germinal centers. Recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription, but the target genes for this activity have not yet been identified. The binding site for BCL-6 shares striking homology to the sites that are the target sequence for the interleukin-4 (IL-4)-induced Stat6 (signal transducers and activators of transcription) signaling molecule. Electrophoretic mobility shift assays demonstrate that BCL-6 can bind, with different affinities, to several DNA elements recognized by Stat6. Expression of BCL-6 can repress the IL-4-dependent induction of immunoglobulin (Ig) germ line epsilon transcripts, but does not repress the IL-4 induction of CD23 transcripts. Consistent with the role of BCL-6 in modulating transcription from the germ line epsilon promoter, BCL-6(-/-) mice display an increased ability to class switch to IgE in response to IL-4 in vitro. These animals also exhibit a multiorgan inflammatory disease characterized by the presence of a large number of IgE(+) B cells. The apparent dysregulation of IgE production is abolished in BCL-6(-/-) Stat6(-/-) mice, indicating that BCL-6 regulation of Ig class switching is dependent upon Stat6 signaling. Thus, BCL-6 can modulate the transcription of selective Stat6-dependent IL-4 responses, including IgE class switching in B cells.

Asunto(s)

Proteínas de Unión al ADN/metabolismo , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/genética , Interleucina-4/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Animales , Linfocitos B/inmunología , Sitios de Unión , Regulación de la Expresión Génica , Células Germinativas/metabolismo , Ratones , Ratones Noqueados , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-6 , Factor de Transcripción STAT6 , Transducción de Señal , Transactivadores/genética , Transcripción Genética