A Dynamic rRNA Ribomethylome Drives Stemness in Acute Myeloid Leukemia

Abstract

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.

The essential roles of small non-coding RNAs and RNA modifications in normal and malignant hematopoiesis

“…Dysfunction on any one of the three snoRNAs: SNORD26, SNORD44, or SNORD78 results in severe morphological abnormalities and embryonic death (Higa-Nakamine et al, 2012). Through a thorough analysis of the rRNA Nm landscape from 94 patients with AML, recent studies also confirmed the plasticity of rRNA Nm that shifts protein translation toward a leukemia stem cell phenotype (Zhou et al, 2023) (Figure 2C). It is interesting to note that in a population of ribosomes, the amounts of modification at the various 2-O methylatable sites are not necessarily the same, but the center of ribosomal subunits frequently contains fully ribomethylated regions.…”

RNA-Guided RNA Modifications: Biogenesis, Functions, and Applications

“…13 Dysregulation of the RNA-guided rRNA 2′methylation machinery has been linked to various human diseases. 14 RNA-guided 2′-O-methylation is also implicated in both major class (U1, U2, U4, U5, and U6) and minor class (U11, U12, U4atac and U6atac) spliceosomal snRNAs, and 18 box C/ D snoRNAs or scaRNAs are involved in modifying these spliceosomal snRNAs. This 2′-O-methylation in snRNAs is crucial for spliceosome assembly, ensuring proper interaction with proteins and other snRNAs as well as RNA splicing.…”

RNA Epigenetics in Chronic Lung Diseases

“…In addition, the methylated reader protein TAR RNA-binding protein (TRBP) binds to the methyltransferase FtsJ RNA 2’-O-methyltransferase 3 (FTSJ3) to form a TRBP-FTSJ3 complex, which induces 2′-O-Me [ 89 ]. Fibrillarin (FBL) is also a 2’-O-methyltransferase that can form a small nucleolar ribonucleoproteins (snoRNPs) with three other proteins and snoRNA for specific rRNA modifications [ 90 ]. Ψ is produced by the isomerization of uridine, catalyzed by pseudouridine synthase (PUS).…”