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 ribo-somal 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-methyl-ation 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.

Automated summary

The dynamic 2'-O-methylation of ribosomal RNA regulates leukemia stem cell activity in acute myeloid leukemia. The methylation pattern is associated with AML development stage and stem cell gene expression. Enhanced 2'-O-methylation redirects ribosome translation and controls AML stem cell self-renewal.