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Nat Cell Biol. 2017 Jul;19(7):844-855. doi: 10.1038/ncb3563. Epub 2017 Jun 26.

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

Author information

1
Department of Hematology and Oncology, University of Halle, Halle 06120, Germany.
2
Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg 69120, Germany.
3
Institute of Molecular Medicine, University of Halle, Halle 06120, Germany.
4
Department of Medicine A, Hematology and Oncology, University of Muenster, Muenster 48149, Germany.
5
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt Am Main 60590, Germany.
6
Department of Hematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
7
German Cancer Research Center and German Cancer, Consortium, Heidelberg 69120, Germany.
8
Division of Genetics, Department of Biology, University of Erlangen-Nuremberg, Erlangen 91058, Germany.
9
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, Ohio 44195, USA.
10
Institute of Medical Immunology, University of Halle, Halle 06120, Germany.
11
Institute of Medical Informatics, University of Muenster, Muenster 48149, Germany.
12
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.
13
Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
14
Broad Institute, Cambridge, Massachusetts 02142, USA.
15
Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
16
Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA.
17
Division of Hematology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada.
18
Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada.
19
Department of Medicine, University of Montreal, Montreal, Quebec H3T 1J4, Canada.
20
Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Quebec H3T 1J4, Canada.

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.

PMID:
28650479
DOI:
10.1038/ncb3563
[Indexed for MEDLINE]

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