A dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia
The development and regulation of malignant self-renewal remain unresolved issues. 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-methy...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
February 06 2023
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| In: |
Cancer discovery
Year: 2023, Jahrgang: 13, Heft: 2, Pages: 332-347 |
| ISSN: | 2159-8290 |
| DOI: | 10.1158/2159-8290.CD-22-0210 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/2159-8290.CD-22-0210
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| Verfasserangaben: | Fengbiao Zhou, Nesrine Aroua, Yi Liu, Christian Rohde, Jingdong Cheng, Anna-Katharina Wirth, Daria Fijalkowska, Stefanie Göllner, Michelle Lotze, Haiyang Yun, Xiaobing Yu, Caroline Pabst, Tim Sauer, Thomas Oellerich, Hubert Serve, Christoph Röllig, Martin Bornhäuser, Christian Thiede, Claudia Baldus, Michaela Frye, Simon Raffel, Jeroen Krijgsveld, Irmela Jeremias, Roland Beckmann, Andreas Trumpp, and Carsten Müller-Tidow |
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| 520 | |a The development and regulation of malignant self-renewal remain unresolved issues. 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 patients with acute myeloid leukemia (AML) revealed dynamic 2′-O-methylation specifically at exterior sites of ribosomes. The rRNA 2′-O-methylation pattern is closely associated with AML development stage and LSC gene expression signature. Forced expression of the 2′-O-methyltransferase fibrillarin (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 toward 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-methylation at specific sites on rRNAs shifts translational preferences and controls AML LSC self-renewal.We establish the complete rRNA 2′-O-methylation landscape in human AML. Plasticity of rRNA 2′-O-methylation shifts protein translation toward an LSC phenotype. This dynamic process constitutes a novel concept of how cancers reprogram cell fate and function.This article is highlighted in the In This Issue feature, p. 247 | ||
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