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Furthermore, deletions of RPL5, RPL11, and RPL22 are frequent in hematologic diseases such as Diamond Blackfan Anemia, T\u2010ALL, multiple myeloma, and in a variety of solid tumors. Yet, the role of these RP defects in dysregulation of the ribosomal translation function remains poorly understood. We engineered an isogenic RiboCancer cell line library modeling the most recurrent RP defects in blood and solid cancers and characterized it by a multi\u2010omics translatome analysis (proteome, Ribo\u2010seq, and total RNA\u2010seq) as well as RiboMethSeq. Within this RiboCancer panel, CLL\n                    <jats:italic>\u2010<\/jats:italic>\n                    associated Rps15 mutations induced the strongest alterations in mRNA translation, affecting up to 10% of expressed genes. Cryo\u2010electron microscopy revealed that these mutations destabilize the Rps15 C\u2010terminus and affect the translation elongation cycle dynamics by deregulating accommodation of aminoacylated tRNAs at the ribosomal A\u2010site. This accommodation defect showed specificity for 11 codons, explaining the reduced translation efficiency of genes with high presence of these codons in Rps15\u2010mutant cells. Notably, these genes were enriched for epigenetic and transcriptional regulators such as transcription factor Runx3, resulting in downregulation of Runx3 target genes involved in immune regulation. By developing and characterizing a unique RiboCancer cell line panel, we mapped translational rewiring driven by the most frequent somatic RP mutations. We provide unprecedented mechanistic insights into translation defects induced by CLL\u2010associated Rps15 mutations, and reveal an intriguing translation\u2010based rewiring of transcription in CLL.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70377","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:26:10Z","timestamp":1780485970000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A RiboCancer cell line panel reveals that CLL\u2010associated Rps15 mutations translationally rewire transcription through codon\u2010specific tRNA accommodation defects"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4130-3588","authenticated-orcid":false,"given":"Ana\u00efs","family":"Astier","sequence":"first","affiliation":[{"name":"University of Toulouse, CNRS, Centre de Biologie Int\u00e9grative Toulouse France"},{"name":"Equipe labellis\u00e9e 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