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Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPU<jats:sup>Low<\/jats:sup> MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1\/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3\u2032\u2010untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU\u2010binding sites restored MM sensitivity to LEN. hnRNPU function in\u00a0vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of <jats:italic>Crbn<\/jats:italic>\u2010humanized murine 5TGM1 cells into <jats:italic>Crbn<\/jats:italic><jats:sup><jats:italic>I391V\/+<\/jats:italic><\/jats:sup> mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation.<\/jats:p>","DOI":"10.1111\/bjh.19468","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T04:26:07Z","timestamp":1714451167000},"page":"594-606","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Decreased <scp>RNA<\/scp>\u2010binding protein <scp>heterogeneous nuclear ribonucleoprotein U<\/scp> improves multiple myeloma sensitivity to lenalidomide"],"prefix":"10.1111","volume":"205","author":[{"given":"Zhimei","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University  Chengdu China"},{"name":"Department of Hematology The Affiliated Hospital of Chengdu University  Chengdu 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