Assuntos
Arsenicais , Leucemia Promielocítica Aguda , Humanos , Trióxido de Arsênio/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Óxidos/farmacologia , Óxidos/uso terapêutico , Proteínas de Fusão Oncogênica/genética , Arsenicais/uso terapêutico , Receptor alfa de Ácido Retinoico , Proteínas RepressorasAssuntos
Células Matadoras Naturais/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Perforina/genética , Infecções por Vírus Epstein-Barr/complicações , Ferritinas/sangue , Fibrinogênio/análise , Hepatite/etiologia , Homozigoto , Humanos , Mutação com Perda de Função , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Mutação de Sentido Incorreto , Perforina/imunologia , Adulto JovemAssuntos
DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Transtornos Linfoproliferativos/diagnóstico , Adulto , Idoso , Linfócitos B/patologia , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/genética , Feminino , Genômica , Humanos , Transtornos Linfoproliferativos/genética , Masculino , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Hibridização de Ácido NucleicoRESUMO
The B-cell non-Hodgkin lymphomas (B-NHL) are a diverse group of haematological malignancies which arise from the mature B-lymphocyte compartment. Recently, our understanding of the molecular pathogenesis of these disorders has greatly increased due to technological advances such as high-throughput DNA sequencing techniques. A paradigm of B-NHL pathogenesis has emerged where the normal genetic processes that are central to generating B-cell receptor diversity (somatic hypermutation and class switch/VDJ recombination) also drive the genesis of large-scale, chromosomal-level genetic lesions and smaller-scale gene-level mutations to produce the malignant phenotypes observed. Whilst a significant degree of genetic heterogeneity exists within each B-NHL subtype, the genetic lesions present within each subtype show a degree of convergence on common intracellular signalling, epigenetic and cell cycle pathways. This convergence gives an insight into the key oncogenic drivers of specific B-NHL subtypes and potential targets for therapeutic intervention. This review covers the current understanding of the causative genetic processes of B-NHL, the associated driving molecular lesions and the implications of these findings for the treatment of this group of disorders.
Assuntos
Linfoma de Células B/etiologia , Linfoma de Células B/metabolismo , Linfoma não Hodgkin/etiologia , Linfoma não Hodgkin/metabolismo , Animais , Aberrações Cromossômicas , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Linfoma de Células B/terapia , Linfoma não Hodgkin/terapia , Mutação , Oncogenes/genéticaRESUMO
Next-generation sequencing techniques are powerful high-throughput methods that have enabled the comprehensive documentation of genetic lesions in numerous hematological malignancies. In recent times, the genomes of multiple different B-cell lymphoproliferative disorders including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, splenic marginal zone lymphoma, mantle cell lymphoma, hairy cell leukemia and Waldenström macroglobulinemia have been documented. Between them, these studies have reinforced and provided insight into the mechanisms for the dysregulation of known pathways (e.g. nuclear factor-κB [NF-κB]), uncovered the importance of new pathways for oncogenesis (e.g. mRNA processing), identified disease-defining mutations and provided meaningful new targets which are already being translated into therapeutic interventions. This review summarizes the molecular lesions that have been discovered in B-cell lymphoproliferative disorders thus far by studies utilizing high-throughput sequencing techniques and the aberrations in the numerous intracellular pathways that have been shown to be involved.
Assuntos
Linfócitos B/metabolismo , Linfócitos B/patologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Processamento Pós-Transcricional do RNA , Transdução de SinaisRESUMO
Hairy cell leukemia has been shown to be strongly associated with the BRAF V600E mutation. We screened 59 unenriched archived bone marrow aspirate and peripheral blood samples from 51 patients with hairy cell leukemia using high resolution melting analysis and confirmatory Sanger sequencing. The BRAF V600E mutation was detected in 38 samples (from 36 patients). The BRAF V600E mutation was detected in all samples with disease involvement above the limit of sensitivity of the techniques used. Thirty-three of 34 samples from other hematologic malignancies were negative for BRAF mutations. A BRAF K601E mutation was detected in a patient with splenic marginal zone lymphoma. Our data support the recent finding of a disease defining point mutation in hairy cell leukemia. Furthermore, high resolution melting with confirmatory Sanger sequencing are useful methods that can be employed in routine diagnostic laboratories to detect BRAF mutations in patients with hairy cell leukemia and related lymphoproliferative disorders.