RESUMO
The putative tumour suppressor gene gravin is down-regulated in several solid tumours and is implicated in tumorigenesis. We have evaluated the expression levels of the gravin gene in the CD34(+)/blast cells of a range of myeloid malignancies as compared with controls using real-time quantitative polymerase chain reaction (PCR). Gravin was markedly down-regulated in 41 of 41 patients with acute myeloid leukaemia (AML), nine of 10 patients with myelodysplastic syndromes (MDS) and 33 of 33 patients with chronic myeloid leukaemia (CML), of whom 24 were in blast crisis (BC). We have shown that gravin is consistently down-regulated in the CD34(+)/blast cells of myeloid malignancies and may play a role in the molecular pathogenesis of these disorders.
Assuntos
Regulação para Baixo , Leucemia Mieloide/genética , Síndromes Mielodisplásicas/genética , Proteínas de Neoplasias/metabolismo , Proteínas/genética , Proteínas de Ancoragem à Quinase A , Doença Aguda , Antígenos CD34/análise , Crise Blástica/genética , Proteínas de Ciclo Celular , Transformação Celular Neoplásica/genética , Análise Mutacional de DNA , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Leucemia Mieloide/genética , Síndromes Mielodisplásicas/genética , Proteínas Tirosina Fosfatases/genética , Doença Aguda , Adulto , Fatores Etários , Criança , Cromossomos Humanos Par 7 , Análise Mutacional de DNA , Éxons/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Monossomia , Reação em Cadeia da Polimerase , Proteína Tirosina Fosfatase não Receptora Tipo 11RESUMO
Mutations of the NRAS and TP53 genes and internal tandem duplication (ITD) of the FLT3 gene are among the most frequently observed molecular abnormalities in the myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We sought to determine the incidence of these abnormalities in patients with MDS and a 5q deletion. NRAS and FLT3 mutations are uncommon in MDS patients with a 5q deletion and TP53 mutation is associated with the more advanced MDS subtypes.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Genes p53 , Genes ras/genética , Síndromes Mielodisplásicas/genética , Tirosina Quinase 3 Semelhante a fms/genética , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal disorders of the haematopoietic stem cell and primarily involve cells of the myeloid lineage. Using cDNA microarrays comprising 6000 human genes, we studied the gene expression profiles in the neutrophils of 21 MDS patients, seven of which had the 5q- syndrome, and two acute myeloid leukaemia (AML) patients when compared with the neutrophils from pooled healthy controls. Data analysis showed a high level of heterogeneity of gene expression between MDS patients, most probably reflecting the underlying karyotypic and genetic heterogeneity. Nevertheless, several genes were commonly up or down-regulated in MDS. The most up-regulated genes included RAB20, ARG1, ZNF183 and ACPL. The RAB20 gene is a member of the Ras gene superfamily and ARG1 promotes cellular proliferation. The most down-regulated genes include COX2, CD18, FOS and IL7R. COX2 is anti-apoptotic and promotes cell survival. Many genes were identified that are differentially expressed in the different MDS subtypes and AML. A subset of genes was able to discriminate patients with the 5q- syndrome from patients with refractory anaemia and a normal karyotype. The microarray expression results for several genes were confirmed by real-time quantitative polymerase chain reaction. The MDS-specific expression changes identified are likely to be biologically important in the pathophysiology of this disorder.
Assuntos
Perfilação da Expressão Gênica/métodos , Síndromes Mielodisplásicas/genética , Neutrófilos/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Regulação para Baixo , Humanos , Família Multigênica , Síndromes Mielodisplásicas/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Regulação para CimaRESUMO
We describe large B cells, many of which have a stellate or dendritic morphology, found in the interfollicular T-cell-rich areas of human peripheral lymphoid tissue. These B cells probably require CD40/CD40 ligand signaling for their generation and have a unique phenotype and a post-germinal center pattern of immunoglobulin gene mutation. The only comparable B cell is the "asteroid" cell of the thymic medulla. Their anatomic location and pattern of gene mutation suggest that these cells may represent the cell of origin of some human large-cell lymphomas. Studies in experimental animals should help to elucidate the role of these cells in the immune response.
Assuntos
Linfócitos B/citologia , Linfócitos B/metabolismo , Dendritos/metabolismo , Antígenos/biossíntese , Antígenos CD40/biossíntese , Ligante de CD40/metabolismo , Citoplasma/metabolismo , Marcadores Genéticos , Genótipo , Humanos , Imunoglobulinas/genética , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/metabolismo , Microscopia de Fluorescência , Modelos Biológicos , Mutação , Fenótipo , Reação em Cadeia da PolimeraseRESUMO
The 5q- syndrome is the most distinct of the myelodysplastic syndromes, and the molecular basis for this disorder remains unknown. We describe the narrowing of the common deleted region (CDR) of the 5q- syndrome to the approximately 1.5-megabases interval at 5q32 flanked by D5S413 and the GLRA1 gene. The Ensembl gene prediction program has been used for the complete genomic annotation of the CDR. The CDR is gene rich and contains 24 known genes and 16 novel (predicted) genes. Of 40 genes in the CDR, 33 are expressed in CD34(+) cells and, therefore, represent candidate genes since they are expressed within the hematopoietic stem/progenitor cell compartment. A number of the genes assigned to the CDR represent good candidates for the 5q- syndrome, including MEGF1, G3BP, and several of the novel gene predictions. These data now afford a comprehensive mutational/expression analysis of all candidate genes assigned to the CDR.
