AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia.
Nat Cell Biol
; 19(7): 844-855, 2017 Jul.
Article
em En
| MEDLINE
| ID: mdl-28650479
ABSTRACT
Leukaemogenesis requires enhanced self-renewal, which is induced by oncogenes. The underlying molecular mechanisms remain incompletely understood. Here, we identified C/D box snoRNAs and rRNA 2'-O-methylation as critical determinants of leukaemic stem cell activity. Leukaemogenesis by AML1-ETO required expression of the groucho-related amino-terminal enhancer of split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, global loss of C/D box snoRNAs with concomitant loss of rRNA 2'-O-methylation resulted in decreased leukaemia self-renewal potential. Genomic deletion of either C/D box snoRNA SNORD14D or SNORD35A suppressed clonogenic potential of leukaemia cells in vitro and delayed leukaemogenesis in vivo. We further showed that AML1-ETO9a, MYC and MLL-AF9 all enhanced snoRNA formation. Expression levels of C/D box snoRNAs in AML patients correlated closely with in vivo frequency of leukaemic stem cells. Collectively, these findings indicate that induction of C/D box snoRNA/RNP function constitutes an important pathway in leukaemogenesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ribonucleoproteínas
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Leucemia
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Proteínas de Fusão Oncogênica
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Transformação Celular Neoplásica
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RNA Nucleolar Pequeno
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Proliferação de Células
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Proteína de Leucina Linfoide-Mieloide
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Subunidade alfa 2 de Fator de Ligação ao Core
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Autorrenovação Celular
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Nat Cell Biol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Alemanha