RESUMEN
PURPOSE: In patients with chronic lymphocytic leukemia (CLL), the VH mutation status and genomic aberrations (13q-, +12q, 11q-, 17p-) identify distinct prognostic subgroups. The aim was to elucidate biologic mechanisms through which these genetic markers may exert their pathogenic influence. PATIENTS AND METHODS: Twenty-four genes involved in apoptosis, cell cycle, B-cell activation, and B-cell receptor (BCR) signaling were analyzed by real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in 82 CLL cases constituting prototypic genetic CLL subgroups as defined by the VH mutation status and the genomic aberrations 13q-, +12, 11q-, and 17p-. RESULTS: The VH mutation subgroups were characterized by a differential expression of the BCR associated genes ZAP70 and PI3K. Among the subgroups defined by genomic aberrations, there was a deregulation of candidate genes from the affected critical genomic regions such as CDK4 (up), ATM (down), and TP53 (down) in the groups +12, 11q-, and 17p-, respectively. Additionally, the genomic subgroups were characterized by a significant deregulation of cell cycle and apoptosis regulators: AKT (up) in 13q, E2F1 (up) in +12, MYC (up) and BCL-2 (down) in 17p-, and CCND3 (down) in 11q- as well as 17p-. The 17p- subgroup showed an additional down-regulation of BCR-associated genes such as SYK and PI3K. CONCLUSION: The characteristic gene expression patterns observed implicate a differential regulation of cell cycle, apoptosis, and BCR signaling in the genetic subgroups illustrating distinct pathomechanisms and are evidence for a gene dosage effect being operative in CLL. These findings link the biologic diversity and clinical heterogeneity of CLL.
Asunto(s)
Apoptosis , Linfocitos B/metabolismo , Biomarcadores de Tumor/metabolismo , Perfilación de la Expresión Génica , Leucemia Linfocítica Crónica de Células B , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal , Aberraciones Cromosómicas , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 17/genética , Dosificación de Gen , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , 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/metabolismo , Activación de Linfocitos , Mutación , Estadificación de Neoplasias , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de SupervivenciaRESUMEN
The B-cell lymphoproliferative malignancies B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) share characteristics, including overlapping chromosomal aberrations with deletions on chromosome bands 13q14, 11q23, 17p13, and 6q21 and gains on chromosome bands 3q26, 12q13, and 8q24. To elucidate the biochemical processes involved in the pathogenesis of B-CLL and MCL, we analyzed the expression level of a set of genes that play central roles in apoptotic or cell proliferation pathways and of candidate genes from frequently altered genomic regions, namely ATM, BAX, BCL2, CCND1, CCND3, CDK2, CDK4, CDKN1A, CDKN1B, E2F1, ETV5, MYC, RB1, SELL, TFDP2, TNFSF10, and TP53. Performing real-time quantitative reverse transcription polymerase chain reaction in a panel of patients with MCL and B-CLL and control samples, significant overexpression and underexpression was observed for most of these genes. Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types. Overexpression in these malignancies suggests ETV5 as a new candidate for a pathogenic factor in B-cell lymphomas. Characteristic deregulation of multiple genes analyzed in this study could be combined in a comprehensive picture of 2 distinctive pathomechanisms in B-CLL and MCL. In B-CLL, the expression parameters are in strong favor of protection of the malignant cells from apoptosis but did not provide evidence for promoting cell cycle. In contrast, in MCL the impairment of apoptosis induction seems to play a minor role, whereas most expression data indicate an enhancement of cell proliferation.
Asunto(s)
Apoptosis/genética , Perfilación de la Expresión Génica/estadística & datos numéricos , Genes cdc , Glucosiltransferasas , Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células del Manto/genética , Proteínas Proto-Oncogénicas , Proteínas de Saccharomyces cerevisiae , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Quinasa 4 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/genética , ADN de Neoplasias/análisis , Proteínas de Unión al ADN/genética , Equinocandinas , Femenino , Proteínas Fúngicas/genética , Humanos , Leucemia Linfocítica Crónica de Células B/etiología , Linfoma de Células del Manto/etiología , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Reacción en Cadena de la Polimerasa/métodos , Factores de Transcripción/genéticaRESUMEN
Sixteen dedifferentiated and pleomorphic liposarcomas were analyzed by comparative genomic hybridization (CGH) to genomic microarrays (matrix-CGH), cDNA-derived microarrays for expression profiling, and by quantitative PCR. Matrix-CGH revealed copy number gains of numerous oncogenes, i.e., CCND1, MDM2, GLI, CDK4, MYB, ESR1, and AIB1, several of which correlate with a high level of transcripts from the respective gene. In addition, a number of genes were found differentially expressed in dedifferentiated and pleomorphic liposarcomas. Application of dedicated clustering algorithms revealed that both tumor subtypes are clearly separated by the genomic profiles but only with a lesser power by the expression profiles. Using a support vector machine, a subset of five clones was identified as "class discriminators." Thus, for the distinction of these types of liposarcomas, genomic profiling appears to be more advantageous than RNA expression analysis.
