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
Intervalo de ano de publicação
1.
Cell Stem Cell ; 19(5): 599-612, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27570067

RESUMO

Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors. In splicing reporter assays and pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. Therapeutic splicing modulation, together with monitoring splice isoform biomarkers of healthy HSPC aging versus LSC generation, may be employed safely and effectively to prevent relapse, the leading cause of leukemia-related mortality.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Splicing de RNA/genética , Animais , Sobrevivência Celular/genética , Senescência Celular/genética , Técnicas de Cocultura , Células HEK293 , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Síndromes Mielodisplásicas/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Spliceossomos/metabolismo , Células Estromais/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA