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Here we show that pseudouridylation (\u03a8) of a stem cell-enriched tRF subtype\n                    <jats:sup>2<\/jats:sup>\n                    , mini tRFs containing a 5\u2032 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-\u03a8 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)\n                    <jats:sup>3<\/jats:sup>\n                    and strongly represses the translation of transcripts sharing pyrimidine-enriched sequences (PES) at the 5\u2032 untranslated region (UTR), including 5\u2032 terminal oligopyrimidine tracts (TOP) that encode protein machinery components and are frequently altered in cancer\n                    <jats:sup>4<\/jats:sup>\n                    . Significantly, mTOG dysregulation leads to aberrantly increased translation of 5\u2032 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 \u03a8 in difficult-to-treat subsets of MDS characterized by high risk of progression to acute myeloid leukaemia (AML).\n                  <\/jats:p>","DOI":"10.1038\/s41556-022-00852-9","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T12:10:52Z","timestamp":1647346252000},"page":"299-306","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["Pseudouridine-modified tRNA fragments repress aberrant protein synthesis and predict leukaemic progression in myelodysplastic syndrome"],"prefix":"10.1038","volume":"24","author":[{"given":"Nicola","family":"Guzzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9110-722X","authenticated-orcid":false,"given":"Sowndarya","family":"Muthukumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Cie\u015bla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6583-3829","authenticated-orcid":false,"given":"Gabriele","family":"Todisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3059-9179","authenticated-orcid":false,"given":"Phuong Cao Thi","family":"Ngoc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3821-3514","authenticated-orcid":false,"given":"Magdalena","family":"Madej","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Munita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Fazio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7694-285X","authenticated-orcid":false,"given":"Simon","family":"Ekstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Mortera-Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Jansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhito","family":"Nannya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6984-8817","authenticated-orcid":false,"given":"Mario","family":"Cazzola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seishi","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1460-1611","authenticated-orcid":false,"given":"Luca","family":"Malcovati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7839-3743","authenticated-orcid":false,"given":"Eva","family":"Hellstr\u00f6m-Lindberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8362-2099","authenticated-orcid":false,"given":"Marios","family":"Dimitriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8047-5329","authenticated-orcid":false,"given":"Cristian","family":"Bellodi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"key":"852_CR1","doi-asserted-by":"crossref","unstructured":"Rosace, D., Lopez, J. & Blanco, S. 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