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TitleA Dynamic rRNA Ribomethylome Drives Stemness in Acute Myeloid Leukemia.
Journal, issue, pagesCancer Discov, Vol. 13, Issue 2, Page 332-347, Year 2023
Publish dateFeb 6, 2023
AuthorsFengbiao 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 / Carsten Müller-Tidow /
PubMed AbstractThe 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- ...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.
SIGNIFICANCE: 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.
External linksCancer Discov / PubMed:36259929 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 2.7 Å
Structure data

33329

7xnx

EMDB-33329, PDB-7xnx:
High resolution cry-EM structure of the human 80S ribosome from SNORD127+/+ Kasumi-1 cells
Method: EM (single particle) / Resolution: 2.7 Å

33330

7xny

EMDB-33330, PDB-7xny:
High resolution cry-EM structure of the human 80S ribosome from SNORD127+/- Kasumi-1 cells
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-K:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • human (human)
KeywordsRIBOSOME / rRNA ribomethylome

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