Journal
NATURE CELL BIOLOGY
Volume 19, Issue 7, Pages 844-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3563
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [MU1328/15-1, MU1328/9-2]
- Deutsche Jose Carreras Leukamie-Stiftung e. V. [DJCLS R10/35f]
- Wilhelm-Roux-Program grant of the Medical Faculty, Martin-Luther-University Halle-Wittenberg [28/43]
- federal state of Saxony-Anhalt [P40]
- Wilhelm Sander Stiftung [2014.054.1]
- Deutsche Krebshilfe [70112282]
- 'Innovative Medical Research' of the University of Munster Medical School (IMF) [121314, 111501]
- Max-Eder grant of the Deutsche Krebshilfe [70111531]
- Deutsche Forschungsgemeinschaft [DFG SL27/7-2]
- DFG [EXC 1003]
- Cancer Research Network of the Fonds de recherche du Quebec-Sante
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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.
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