TY  - JOUR
AU  - Zhou, Fengbiao
AU  - Aroua, Nesrine
AU  - Liu, Yi
AU  - Rohde, Christian
AU  - Cheng, Jingdong
AU  - Wirth, Anna-Katharina
AU  - Fijalkowska, Daria
AU  - Göllner, Stefanie
AU  - Lotze, Michelle
AU  - Yun, Haiyang
AU  - Yu, Xiaobing
AU  - Pabst, Caroline
AU  - Sauer, Tim
AU  - Oellerich, Thomas
AU  - Serve, Hubert
AU  - Rollig, Christoph
AU  - Bornhauser, Martin
AU  - Thiede, Christian
AU  - Baldus, Claudia
AU  - Frye, Michaela
AU  - Raffel, Simon
AU  - Krijgsveld, Jeroen
AU  - Jeremias, Irmela
AU  - Beckmann, Roland
AU  - Trumpp, Andreas
AU  - Muller-Tidow, Carsten
TI  - A dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia.
JO  - Cancer discovery
VL  - 13
IS  - 2
SN  - 2159-8274
CY  - Philadelphia, Pa.
M1  - DKFZ-2022-02474
SP  - 332-347
PY  - 2023
N1  - #EA:A010#LA:A010# / 2023 Feb 6;13(2):332-347
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36259929
DO  - DOI:10.1158/2159-8290.CD-22-0210
UR  - https://inrepo02.dkfz.de/record/182171
ER  -