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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)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Protein-synthesis; Gene-expression; Self-renewal; Codon Optimality; Translation; Cells; Differentiation; Methylation; Cancer; Quantification
Language english
Publication Year 2023
Prepublished in Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 2159-8274
e-ISSN 2159-8290
Journal Cancer Discovery
Quellenangaben Volume: 13, Issue: 2, Pages: 1–17 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place Philadelphia, Pa.
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Stem Cell and Neuroscience
PSP Element(s) G-506600-001
Grants 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)
DOI 10.1158/2159-8290.CD-22-0210
WOS ID 001185376200027
WOS ID 000941831400001
WOS ID 001142881400005
PubMed ID 36259929
Erfassungsdatum 2022-10-25
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