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1.
Immunity ; 42(1): 186-98, 2015 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-25607463

RESUMEN

Most B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions REs from normal GC B cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated in FL, targeted commandeered versus decommissioned REs. Our approach revealed two distinct subtypes of low-grade FL, whose pathogenic circuitries resembled GC B or activated B cells. FL-altered enhancers also were enriched for sequence variants, including somatic mutations, which disrupt transcription-factor binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation.


Asunto(s)
Linfocitos B/fisiología , Redes Reguladoras de Genes , Centro Germinal/patología , Linfoma de Células B/genética , Elementos Reguladores de la Transcripción/inmunología , Adulto , Anciano , Transformación Celular Neoplásica , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Activación de Linfocitos/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Elementos Reguladores de la Transcripción/genética , Factores de Transcripción/metabolismo
2.
EBioMedicine ; 71: 103559, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34461601

RESUMEN

BACKGROUND: The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping "cell-of-origin". Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry. METHODS: We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays). FINDINGS: From the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR. More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2(POU2F2), and RUNX3. Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation. INTERPRETATION: Our study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma. FUNDING: National Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation.


Asunto(s)
Linfocitos B/metabolismo , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Leucemia de Células B/etiología , Linfoma de Células B/etiología , Transcripción Genética , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , Biomarcadores , Transformación Celular Neoplásica/metabolismo , Secuenciación de Inmunoprecipitación de Cromatina , Biología Computacional/métodos , Variaciones en el Número de Copia de ADN , Elementos de Facilitación Genéticos , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Leucemia de Células B/diagnóstico , Leucemia de Células B/metabolismo , Linfoma de Células B/diagnóstico , Linfoma de Células B/metabolismo , Masculino , Persona de Mediana Edad , Modelos Biológicos , Oncogenes , Transducción de Señal , Factores de Transcripción/metabolismo
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