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1.
Clin Epigenetics ; 11(1): 177, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791414

RESUMO

BACKGROUND: In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen. RESULTS: The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed "epigenetic burden" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed "relapse changes" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology. CONCLUSIONS: Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.

2.
Nat Med ; 24(6): 868-880, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29785028

RESUMO

Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.


Assuntos
Cromatina/metabolismo , Epigenômica , Leucemia Linfocítica Crônica de Células B/genética , Linfócitos B/metabolismo , Sequência de Bases , Estudos de Coortes , Humanos
3.
Cancer Cell ; 30(5): 806-821, 2016 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-27846393

RESUMO

We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.


Assuntos
Metilação de DNA , Elementos Facilitadores Genéticos , Epigenômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linfoma de Célula do Manto/genética , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula , Simulação por Computador , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição SOXC/genética
4.
Cell Rep ; 13(5): 1059-71, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26565917

RESUMO

Molecular mechanisms underlying terminal differentiation of B cells into plasma cells are major determinants of adaptive immunity but remain only partially understood. Here we present the transcriptional and epigenomic landscapes of cell subsets arising from activation of human naive B cells and differentiation into plasmablasts. Cell proliferation of activated B cells was linked to a slight decrease in DNA methylation levels, but followed by a committal step in which an S phase-synchronized differentiation switch was associated with an extensive DNA demethylation and local acquisition of 5-hydroxymethylcytosine at enhancers and genes related to plasma cell identity. Downregulation of both TGF-?1/SMAD3 signaling and p53 pathway supported this final step, allowing the emergence of a CD23-negative subpopulation in transition from B cells to plasma cells. Remarkably, hydroxymethylation of PRDM1, a gene essential for plasma cell fate, was coupled to progression in S phase, revealing an intricate connection among cell cycle, DNA (hydroxy)methylation, and cell fate determination.


Assuntos
Ciclo Celular , Metilação de DNA , Linfopoese , Plasmócitos/citologia , Células Cultivadas , Humanos , Plasmócitos/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptores de IgE/genética , Receptores de IgE/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
5.
Genes Chromosomes Cancer ; 54(11): 668-80, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26305789

RESUMO

Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk-adapted therapy. We have developed a targeted genome-wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4-marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip®Hemo array with a high density of probes covering commonly altered loci in CLL (11q22-q23, 13q14, and 17p13), nine focal regions (2p15-p16.1, 2p24.3, 2q13, 2q36.3-q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32-q21.33) and two larger regions (6q14.1-q22.31 and 7q31.33-q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis-like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P = 0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P < 0.001, P = 0.001, and P = 0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials.


Assuntos
Aberrações Cromossômicas , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Dosagem de Genes , Genoma Humano , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos/métodos
6.
Nature ; 526(7574): 519-24, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26200345

RESUMO

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Regiões 3' não Traduzidas/genética , Processamento Alternativo/genética , Linfócitos B/metabolismo , Proteínas de Transporte/genética , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Elementos Facilitadores Genéticos/genética , Genômica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fator de Transcrição PAX5/biossíntese , Fator de Transcrição PAX5/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fatores de Transcrição/genética
7.
Nat Genet ; 47(7): 746-56, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26053498

RESUMO

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.


Assuntos
Linfócitos B/fisiologia , Metilação de DNA , Epigênese Genética/imunologia , Sequência de Bases , Diferenciação Celular , Células Cultivadas , Ilhas de CpG , Regulação Leucêmica da Expressão Gênica , Genoma Humano , Humanos , Leucemia de Células B/genética , Análise de Sequência de DNA
8.
Genome Res ; 25(4): 478-87, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25644835

RESUMO

While analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM.


Assuntos
Metilação de DNA/genética , Elementos Facilitadores Genéticos/genética , Mieloma Múltiplo/genética , Células-Tronco Neoplásicas/citologia , Plasmócitos/citologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Ilhas de CpG/genética , DNA de Neoplasias/genética , Regulação para Baixo/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Humanos , Regiões Promotoras Genéticas , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
9.
Biochim Biophys Acta ; 1829(11): 1161-74, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23938249

RESUMO

Ever since the discovery of DNA methylation at cytosine residues, the role of this so called fifth base has been extensively studied and debated. Until recently, the majority of DNA methylation studies focused on the analysis of CpG islands associated to promoter regions. However, with the upcoming possibilities to study DNA methylation in a genome-wide context, this epigenetic mark can now be studied in an unbiased manner. As a result, recent studies have shown that not only promoters but also intragenic and intergenic regions are widely modulated during physiological processes and disease. In particular, it is becoming increasingly clear that DNA methylation in the gene body is not just a passive witness of gene transcription but it seems to be actively involved in multiple gene regulation processes. In this review we discuss the potential role of intragenic DNA methylation in alternative promoter usage, regulation of short and long non-coding RNAs, alternative RNA processing, as well as enhancer activity. Furthermore, we summarize how the intragenic DNA methylome is modified both during normal cell differentiation and neoplastic transformation.


Assuntos
Diferenciação Celular/genética , Metilação de DNA , Regulação da Expressão Gênica , Neoplasias/genética , Transcrição Genética , Elementos de DNA Transponíveis , Elementos Facilitadores Genéticos , Humanos , Neoplasias/patologia , Regiões Promotoras Genéticas , Processamento Pós-Transcricional do RNA
10.
J Clin Immunol ; 33(2): 349-60, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23064977

RESUMO

PURPOSE: Intravenous IgG (ivIg) is a therapeutic alternative for lupus erythematosus, the mechanism of which remains to be fully understood. Here we investigated whether ivIg affects two established sub-phenotypes of SLE, namely relative oligoclonality of circulating T-cells and reduced activity of CD4 + Foxp3+ regulatory T-cells (Tregs) reflected by lower CD25 surface density. METHODS: We conducted a longitudinal study of 15 lupus patients (14 with SLE and one with discoid LE) treated with ivIg in cycles of 2-6 consecutive monthly infusions. Among these 15 patients, 10 responded to ivIg therapy with clear clinical improvement. We characterized Tregs and determined TCR spectratypes of four Vß families with reported oligoclonality. Cell counts, cytometry and TCR spectratypes were obtained from peripheral blood at various time points before, during and after ivIg treatment. T-cell oligoclonality was assessed as Vß-familywise repertoire perturbation, calculated for each patient in respect to an individual reference profile averaged over all available time points. RESULTS: For 11 out of 15 patients, average Vß1/Vß2/Vß11/Vß14 repertoires were less perturbed under than outside ivIg therapy. The four exceptions with relatively increased average perturbation during ivIg therapy included three patients who failed to respond clinically to an ivIg therapy cycle. Patients' Treg CD25 surface density (cytometric MFI) was clearly reduced when compared to healthy controls, but not obviously influenced by ivIg. However, patients' average Treg CD25 MFI was found negatively correlated with both Vß11 and Vß14 perturbations measured under ivIg therapy. CONCLUSIONS: This indicates a role of active Tregs in the therapeutic effect of ivIg.


Assuntos
Imunoglobulinas Intravenosas , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Estudos Longitudinais , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto Jovem
11.
Nat Genet ; 44(11): 1236-42, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23064414

RESUMO

We have extensively characterized the DNA methylomes of 139 patients with chronic lymphocytic leukemia (CLL) with mutated or unmutated IGHV and of several mature B-cell subpopulations through the use of whole-genome bisulfite sequencing and high-density microarrays. The two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B-cell subpopulations. DNA hypomethylation in the gene body, targeting mostly enhancer sites, was the most frequent difference between naive and memory B cells and between the two molecular subtypes of CLL and normal B cells. Although DNA methylation and gene expression were poorly correlated, we identified gene-body CpG dinucleotides whose methylation was positively or negatively associated with expression. We have also recognized a DNA methylation signature that distinguishes new clinico-biological subtypes of CLL. We propose an epigenomic scenario in which differential methylation in the gene body may have functional and clinical implications in leukemogenesis.


Assuntos
Linfócitos B/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo , Ilhas de CpG/genética , Feminino , Regulação da Expressão Gênica , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade
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