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AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia

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 requi...

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Main Authors: Zhou, Fengbiao (Author) , Liu, Yi (Author) , Rohde, Christian (Author) , Pauli, Cornelius (Author) , Gerloff, Dennis (Author) , Köhn, Marcel (Author) , Misiak, Danny (Author) , Bäumer, Nicole (Author) , Cui, Chunhong (Author) , Göllner, Stefanie (Author) , Oellerich, Thomas (Author) , Serve, Hubert (Author) , Garcia-Cuellar, Maria-Paz (Author) , Slany, Robert (Author) , Maciejewski, Jaroslaw P. (Author) , Przychodzen, Bartlomiej (Author) , Seliger, Barbara (Author) , Klein, Hans-Ulrich (Author) , Bartenhagen, Christoph (Author) , Berdel, Wolfgang E. (Author) , Dugas, Martin (Author) , Taketo, Makoto Mark (Author) , Farouq, Daneyal (Author) , Schwartz, Schraga (Author) , Regev, Aviv (Author) , Hébert, Josée (Author) , Sauvageau, Guy (Author) , Pabst, Caroline (Author) , Hüttelmaier, Stefan (Author) , Müller-Tidow, Carsten (Author)
Format: Article (Journal)
Language:English
Published: 26 June 2017
In: Nature cell biology
Year: 2017, Volume: 19, Issue: 7, Pages: 844-855
ISSN:1476-4679
DOI:10.1038/ncb3563
Online Access:Verlag, Volltext: http://dx.doi.org/10.1038/ncb3563
Verlag, Volltext: https://www.nature.com/articles/ncb3563
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Author Notes:Fengbiao Zhou, Yi Liu, Christian Rohde, Cornelius Pauli, Dennis Gerloff, Marcel Köhn, Danny Misiak, Nicole Bäumer, Chunhong Cui, Stefanie Göllner, Thomas Oellerich, Hubert Serve, Maria-Paz Garcia-Cuellar, Robert Slany, Jaroslaw P. Maciejewski, Bartlomiej Przychodzen, Barbara Seliger, Hans-Ulrich Klein, Christoph Bartenhagen, Wolfgang E. Berdel, Martin Dugas, Makoto Mark Taketo, Daneyal Farouq, Schraga Schwartz, Aviv Regev, Josée Hébert, Guy Sauvageau, Caroline Pabst, Stefan Hüttelmaier and Carsten Müller-Tidow
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Summary: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.
Item Description:Gesehen am 09.08.2018
Physical Description:Online Resource
ISSN:1476-4679
DOI:10.1038/ncb3563

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