Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome

Transfer RNA-derived fragments (tRFs) are emerging small noncoding RNAs that, although commonly altered in cancer, have poorly defined roles in tumorigenesis(1). Here we show that pseudouridylation (Psi) of a stem cell-enriched tRF subtype(2), mini tRFs containing a 5' terminal oligoguanine (mTOG), selectively inhibits aberrant protein synthesis programmes, thereby promoting engraftment and differentiation of haematopoietic stem and progenitor cells (HSPCs) in patients with myelodysplastic syndrome (MDS). Building on evidence that mTOG-Psi targets polyadenylate-binding protein cytoplasmic 1 (PABPC1), we employed isotope exchange proteomics to reveal critical interactions between mTOG and functional RNA-recognition motif (RRM) domains of PABPC1. Mechanistically, this hinders the recruitment of translational co-activator PABPC1-interacting protein 1 (PAIP1)(3) and strongly represses the translation of transcripts sharing pyrimidine-enriched sequences (PES) at the 5' untranslated region (UTR), including 5' terminal oligopyrimidine tracts (TOP) that encode protein machinery components and are frequently altered in cancer(4). Significantly, mTOG dysregulation leads to aberrantly increased translation of 5' PES messenger RNA (mRNA) in malignant MDS-HSPCs and is clinically associated with leukaemic transformation and reduced patient survival. These findings define a critical role for tRFs and. in difficult-to-treat subsets of MDS characterized by high risk of progression to acute myeloid leukaemia (AML).

Automated summary

This study demonstrates that pseudouridylation of a stem cell-enriched tRF subtype, mini tRFs containing a 5' terminal oligoguanine (mTOG), selectively inhibits aberrant protein synthesis programs, thereby promoting engraftment and differentiation of hematopoietic stem and progenitor cells in MDS patients. The mechanism involves hindering the recruitment of translational co-activator PAIP1 and repressing translation of transcripts sharing pyrimidine-enriched sequences at the 5' UTR, including TOP sequences frequently altered in cancer. Dysregulation of mTOG leads to increased translation of 5' PES mRNA in malignant MDS-HSPCs, which is associated with leukaemic transformation and reduced patient survival.