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

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; Carsten Müller-Tidow

doi:10.1038/ncb3563

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

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

Authors

Fengbiao Zhou^{1

2}, Yi Liu^{1

2}, Christian Rohde^{1

2}, Cornelius Pauli¹, Dennis Gerloff¹, Marcel Köhn³, Danny Misiak³, Nicole Bäumer⁴, Chunhong Cui¹, Stefanie Göllner^{1

2}, Thomas Oellerich^{5

6

7}, Hubert Serve^{5

7}, Maria-Paz Garcia-Cuellar⁸, Robert Slany⁸, Jaroslaw P Maciejewski⁹, Bartlomiej Przychodzen⁹, Barbara Seliger¹⁰, Hans-Ulrich Klein^{11

12}, Christoph Bartenhagen¹¹, Wolfgang E Berdel⁴, Martin Dugas¹¹, Makoto Mark Taketo¹³, Daneyal Farouq¹⁴, Schraga Schwartz¹⁴, Aviv Regev^{14

15

16}, Josée Hébert^{17

18

19}, Guy Sauvageau^{18

19

20}, Caroline Pabst^{1

2}, Stefan Hüttelmaier³, Carsten Müller-Tidow^{1

2}

Affiliations

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.

PMID: 28650479
DOI: 10.1038/ncb3563

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.

MeSH terms

Animals
Cell Proliferation*
Cell Self Renewal*
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Co-Repressor Proteins
Core Binding Factor Alpha 2 Subunit / genetics
Core Binding Factor Alpha 2 Subunit / metabolism*
DEAD-box RNA Helicases / genetics
DEAD-box RNA Helicases / metabolism
Gene Expression Regulation, Leukemic
Genetic Predisposition to Disease
HEK293 Cells
HL-60 Cells
Humans
K562 Cells
Leukemia / genetics
Leukemia / metabolism*
Leukemia / pathology
Methylation
Mice, Inbred C57BL
Mice, Knockout
Myeloid-Lymphoid Leukemia Protein / genetics
Myeloid-Lymphoid Leukemia Protein / metabolism*
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism*
Phenotype
Protein Interaction Maps
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA, Ribosomal / genetics
RNA, Ribosomal / metabolism
RNA, Small Nucleolar / genetics
RNA, Small Nucleolar / metabolism*
RUNX1 Translocation Partner 1 Protein
Repressor Proteins / genetics
Repressor Proteins / metabolism
Ribonucleoproteins / genetics
Ribonucleoproteins / metabolism*
Signal Transduction
Time Factors
Transcription Factors / genetics
Transcription Factors / metabolism
U937 Cells

Substances

AML1-ETO fusion protein, human
AML1-ETO fusion protein, mouse
Co-Repressor Proteins
Core Binding Factor Alpha 2 Subunit
MLL-AF9 fusion protein, human
MYC protein, human
Oncogene Proteins, Fusion
Proto-Oncogene Proteins c-myc
RNA, Ribosomal
RNA, Small Nucleolar
RUNX1 Translocation Partner 1 Protein
Repressor Proteins
Ribonucleoproteins
TLE5 protein, human
Tle5 protein, mouse
Transcription Factors
Myeloid-Lymphoid Leukemia Protein
DDX21 protein, human
DEAD-box RNA Helicases