RESUMEN
The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression "signature," irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.
Asunto(s)
Expresión Génica , Inmunoglobulinas/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Genotipo , Humanos , InmunofenotipificaciónRESUMEN
A comparative analysis of the genomes of Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae-and the proteins they are predicted to encode-was undertaken in the context of cellular, developmental, and evolutionary processes. The nonredundant protein sets of flies and worms are similar in size and are only twice that of yeast, but different gene families are expanded in each genome, and the multidomain proteins and signaling pathways of the fly and worm are far more complex than those of yeast. The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.
Asunto(s)
Caenorhabditis elegans/genética , Drosophila melanogaster/genética , Genoma , Proteoma , Saccharomyces cerevisiae/genética , Animales , Apoptosis/genética , Evolución Biológica , Caenorhabditis elegans/química , Caenorhabditis elegans/fisiología , Adhesión Celular/genética , Ciclo Celular/genética , Drosophila melanogaster/química , Drosophila melanogaster/fisiología , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Genes Duplicados , Enfermedades Genéticas Congénitas/genética , Genética Médica , Proteínas del Helminto/química , Proteínas del Helminto/genética , Humanos , Inmunidad/genética , Proteínas de Insectos/química , Proteínas de Insectos/genética , Familia de Multigenes , Neoplasias/genética , Estructura Terciaria de Proteína , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/fisiología , Transducción de Señal/genéticaRESUMEN
We have curated a reference set of cancer- related genes and reanalyzed their sequences in the light of molecular information and resources that have become available since they were first cloned. Homology studies were carried out for human oncogenes and tumor suppressors, compared with the complete proteome of the nematode, Caenorhabditis elegans, and partial proteomes of mouse and rat and the fruit fly, Drosophila melanogaster. Our results demonstrate that simple, semi-automated bioinformatics approaches to identifying putative functionally equivalent gene products in different organisms may often be misleading. An electronic supplement to this article provides an integrated view of our comparative genomics analysis as well as mapping data, physical cDNA resources and links to published literature and reviews, thus creating a "window" into the genomes of humans and other organisms for cancer biology.
Asunto(s)
Genes Supresores de Tumor , Genoma , Oncogenes , Animales , Caenorhabditis/genética , Drosophila melanogaster/genética , Proyecto Genoma Humano , Humanos , Ratones , RatasRESUMEN
Human L1 retrotransposons can produce DNA transduction events in which unique DNA segments downstream of L1 elements are mobilized as part of aberrant retrotransposition events. That L1s are capable of carrying out such a reaction in tissue culture cells was elegantly demonstrated. Using bioinformatic approaches to analyze the structures of L1 element target site duplications and flanking sequence features, we provide evidence suggesting that approximately 15% of full-length L1 elements bear evidence of flanking DNA segment transduction. Extrapolating these findings to the 600,000 copies of L1 in the genome, we predict that the amount of DNA transduced by L1 represents approximately 1% of the genome, a fraction comparable with that occupied by exons.
Asunto(s)
ADN/genética , ADN/metabolismo , Elementos de Nucleótido Esparcido Largo/genética , Mutagénesis Insercional/genética , Regiones no Traducidas 3'/genética , Biología Computacional/métodos , Humanos , Modelos BiológicosRESUMEN
A compendium of global gene expression measurements from DNA microarray analysis of immune cells identifies gene expression signatures defining various lineages, differentiation stages, and signaling pathways. Germinal center (GC) B cells represent a discrete stage of differentiation with a unique gene expression signature. This includes genes involved in proliferation, as evidenced by high expression of G2/M phase regulators and low expression of ribosomal and metabolic genes that are transcriptional targets of c-myc. GC B cells also lack expression of the NF-kappaB signature genes, which may favor apoptosis. Finally, the transcriptional repression signature of BCL-6 reveals how this factor can prevent terminal differentiation of B cells and cause B cell lymphomas.
Asunto(s)
Linfocitos B/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Linfocitos T/fisiología , Animales , Señalización del Calcio , Linaje de la Célula , Humanos , Activación de Linfocitos , FN-kappa B/metabolismo , ARN Mensajero/químicaRESUMEN
BACKGROUND: Flavopiridol, a flavonoid currently in cancer clinical trials, inhibits cyclin-dependent kinases (CDKs) by competitively blocking their ATP-binding pocket. However, the mechanism of action of flavopiridol as an anti-cancer agent has not been fully elucidated. RESULTS: Using DNA microarrays, we found that flavopiridol inhibited gene expression broadly, in contrast to two other CDK inhibitors, roscovitine and 9-nitropaullone. The gene expression profile of flavopiridol closely resembled the profiles of two transcription inhibitors, actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB), suggesting that flavopiridol inhibits transcription globally. We were therefore able to use flavopiridol to measure mRNA turnover rates comprehensively and we found that different functional classes of genes had distinct distributions of mRNA turnover rates. In particular, genes encoding apoptosis regulators frequently had very short half-lives, as did several genes encoding key cell-cycle regulators. Strikingly, genes that were transcriptionally inducible were disproportionately represented in the class of genes with rapid mRNA turnover. CONCLUSIONS: The present genomic-scale measurement of mRNA turnover uncovered a regulatory logic that links gene function with mRNA half-life. The observation that transcriptionally inducible genes often have short mRNA half-lives demonstrates that cells have a coordinated strategy to rapidly modulate the mRNA levels of these genes. In addition, the present results suggest that flavopiridol may be more effective against types of cancer that are highly dependent on genes with unstable mRNAs.