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As it remains unclear how these differences reflect the tumour cells\u2019 innate pre\/post germinal centre origin or their BCR signalling competence, we applied mRNA\/miRNA sequencing to 38 CLL cases categorised into three subsets by IGHV mutational status and BCR signalling capacity. We identified 492 mRNAs and 38 miRNAs differentially expressed between U-CLL and M-CLL, but only 9 mRNAs and 0 miRNAs associated with BCR competence within M-CLL. Of the IGHV-associated miRNAs, (14\/38 (37%)) derived from chr14q32 clusters where all miRNAs were co-expressed with the\n                    <jats:italic>MEG3<\/jats:italic>\n                    lncRNA from a cancer associated imprinted locus. Integrative analysis of miRNA\/mRNA data revealed pronounced regulatory potential for the 14q32 miRNAs, potentially accounting for up to 25% of the IGHV-related transcriptome signature.\n                    <jats:italic>GAB1<\/jats:italic>\n                    , a positive regulator of BCR signalling, was potentially regulated by five 14q32 miRNAs and we confirmed that two of these (miR-409-3p and miR-411-3p) significantly repressed activity of the\n                    <jats:italic>GAB1<\/jats:italic>\n                    3\u2032UTR. Our analysis demonstrates a potential key role of the 14q32 miRNA locus in the regulation of CLL-related gene regulation.\n                  <\/jats:p>","DOI":"10.1038\/s41375-023-01918-9","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T08:02:59Z","timestamp":1683792179000},"page":"1454-1463","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Network analysis reveals a major role for 14q32 cluster miRNAs in determining transcriptional differences between IGHV-mutated and unmutated CLL"],"prefix":"10.1038","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3163-608X","authenticated-orcid":false,"given":"Dean","family":"Bryant","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karly Rai","family":"Rogers-Broadway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Karydis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongmin","family":"Woo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1099-3985","authenticated-orcid":false,"given":"Matthew D.","family":"Blunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2211-1831","authenticated-orcid":false,"given":"Francesco","family":"Forconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0933-5021","authenticated-orcid":false,"given":"Freda K.","family":"Stevenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Goodnow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7148-1081","authenticated-orcid":false,"given":"Amanda","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3331-6496","authenticated-orcid":false,"given":"Peter","family":"Humburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Packham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Steele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0972-2881","authenticated-orcid":false,"given":"Jonathan C.","family":"Strefford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"1918_CR1","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1182\/blood.V94.6.1848","volume":"94","author":"TJ Hamblin","year":"1999","unstructured":"Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. 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JS declares the following competing interests: Research funding: Roche Holding AG and Cambridge Epigenetix. AJS declares the following competing interests: Current employee of Janssen Pharmaceutical Companies of Johnson and Johnson. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}