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Zhou, F.* ; Aroua, N.* ; Liu, Y.* ; Rohde, C.* ; Cheng, J.* ; Wirth, A.-K. ; Fijalkowska, D.* ; Göllner, S.* ; Lotze, M.T.* ; Yun, H.* ; Yu, X.* ; Pabst, C.* ; Sauer, T.* ; Oellerich, T.* ; Serve, H.* ; Röllig, C.* ; Bornhäuser, M.* ; Thiede, C.* ; Baldus, C.* ; Frye, M.* ; Raffel, S.* ; Krijgsveld, J.* ; Jeremias, I. ; Beckmann, R.* ; Trumpp, A.* ; Müller-Tidow, C.*

A dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia.

Cancer Discov. 13, 1–17 (2023)
Verlagsversion Postprint DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
The development and regulation of malignant self-renewal remains an unresolved issue. Here, we provide biochemical, genetic, and functional evidence that dynamics in ribosomal RNA (rRNA) 2'-O-methylation regulate leukemia stem cell (LSC) activity in vivo. A comprehensive analysis of the rRNA 2'-O-methylation landscape of 94 acute myeloid leukemia (AML) patients revealed dynamic 2'-O-methylation specifically at exterior sites of ribosomes. rRNA 2'-O-methylation pattern is closely associated with AML development stage and LSC gene expression signature. Forced expression of 2'-O-methyltransferase FBL induced an AML stem cell phenotype and enabled engraftment of non-LSC leukemia cells in NSG mice. Enhanced 2'-O-methylation redirected the ribosome translation program towards amino acid transporter mRNAs enriched in optimal codons and subsequently increased intracellular amino acid levels. Methylation at the single site 18S-guanosine 1447 was instrumental for LSC activity. Collectively, our work demonstrates that dynamic 2'-O-Me at specific sites on ribosomal RNAs shifts translational preferences and controls AML-LSC self-renewal.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Protein-synthesis; Gene-expression; Self-renewal; Codon Optimality; Translation; Cells; Differentiation; Methylation; Cancer; Quantification
ISSN (print) / ISBN 2159-8274
e-ISSN 2159-8290
Zeitschrift Cancer Discovery
Quellenangaben Band: 13, Heft: 2, Seiten: 1–17 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Verlagsort Philadelphia, Pa.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Förderungen Deutsche Krebshilfe
Deutsche Forschungsgemeinschaft (DFG)
Deutsche Jose-Carreras-Leukaemie-Stiftung
Sander Stiftung
BMBF
European Research Council
DKTK joint funding project "RiskY-AML"
Dietmar Hopp Foundation
European Research Council (ERC)