Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros

Banco de datos
Tipo de estudio
Tipo del documento
Asunto de la revista
País de afiliación
Intervalo de año de publicación
1.
Blood ; 127(22): 2732-41, 2016 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-27048211

RESUMEN

The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-κB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-κB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2 Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2 Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL.


Asunto(s)
Linfocitos B/metabolismo , Transformación Celular Neoplásica/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Mutación Missense , Factor 88 de Diferenciación Mieloide/biosíntesis , Neoplasias Experimentales/metabolismo , Animales , Linfocitos B/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones Transgénicos , Factor 88 de Diferenciación Mieloide/genética , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/genética
2.
Nat Commun ; 8(1): 153, 2017 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-28751718

RESUMEN

Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge. Here we generated two mouse models of Atm- and Trp53-deficient CLL. These animals display a significantly earlier disease onset and reduced overall survival, compared to controls. We employed these models in conjunction with transcriptome analyses following cyclophosphamide treatment to reveal that Atm deficiency is associated with an exquisite and genotype-specific sensitivity against PARP inhibition. Thus, we generate two aggressive CLL models and provide a preclinical rational for the use of PARP inhibitors in ATM-affected human CLL.ATM and TP53 mutations are associated with poor prognosis in chronic lymphocytic leukaemia (CLL). Here the authors generate mouse models of Tp53- and Atm-defective CLL mimicking the high-risk form of human disease and show that Atm-deficient CLL is sensitive to PARP1 inhibition.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Modelos Animales de Enfermedad , Leucemia Linfocítica Crónica de Células B/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 17/genética , Ciclofosfamida/farmacología , Perfilación de la Expresión Génica/métodos , Humanos , Immunoblotting , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA