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
de 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Ribonucléoprotéines
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Leucémies
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Protéines de fusion oncogènes
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Transformation cellulaire néoplasique
/
Petit ARN nucléolaire
/
Prolifération cellulaire
/
Protéine de la leucémie myéloïde-lymphoïde
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Sous-unité alpha 2 du facteur CBF
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Auto-renouvellement cellulaire
Type d'étude:
Prognostic_studies
Langue:
En
Journal:
Nat Cell Biol
Année:
2017
Type de document:
Article
Pays d'affiliation:
Allemagne