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

Base de dados
Ano de publicação
Tipo de documento
Assunto da revista
País de afiliação
Intervalo de ano de publicação
1.
Genes Dev ; 25(15): 1628-40, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21828272

RESUMO

Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations-a phenomenon dubbed "oncogene addiction." Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9-a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo.


Assuntos
Regulação Neoplásica da Expressão Gênica , Leucemia/fisiopatologia , Oncogenes/fisiologia , Proteínas Proto-Oncogênicas c-myb/metabolismo , Animais , Modelos Animais de Doenças , Genes myb/genética , Hematopoese , Camundongos , Proteínas de Fusão Oncogênica/metabolismo , Oncogenes/genética , Proteínas Proto-Oncogênicas c-myb/genética , Interferência de RNA
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA