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By ATAC\u2010seq, chromatin regions that were more accessible in <jats:italic>XPO1<\/jats:italic> mutated CLL were enriched of binding sites for transcription factors regulated by pathways emanating from the B\u2010cell receptor (BCR), including NF\u2010\u03baB signalling, p38\u2010JNK and RAS\u2010RAF\u2010MEK\u2010ERK. <jats:italic>XPO1<\/jats:italic> mutant CLL, consistent with the chromatin accessibility changes, were enriched with transcriptomic features associated with BCR and cytokine signalling. By combining epigenomic and transcriptomic data, <jats:italic>MIR155HG<\/jats:italic>, the host gene of miR\u2010155, and <jats:italic>MYB<\/jats:italic>, the transcription factor that positively regulates MIR155HG, were upregulated by RNA\u2010seq and their promoters were more accessible by ATAC\u2010seq. To evaluate the clinical impact of <jats:italic>XPO1<\/jats:italic> mutations, we investigated a total of 957 early\u2010stage CLL subdivided into 3 independent cohorts (<jats:italic>N<\/jats:italic>\u2009=\u2009276, <jats:italic>N<\/jats:italic>\u2009=\u2009286 and <jats:italic>N<\/jats:italic>\u2009=\u2009395). Next\u2010generation sequencing analysis identified <jats:italic>XPO1<\/jats:italic> mutations as a novel predictor of shorter time to first treatment (TTFT) in all cohorts. Notably, <jats:italic>XPO1<\/jats:italic> mutations maintained their prognostic value independent of the immunoglobulin heavy chain variable status and early\u2010stage prognostic models. These data suggest that <jats:italic>XPO1<\/jats:italic> mutations, conceivably through increased miR\u2010155 levels, may enhance BCR signalling leading to higher proliferation and shorter TTFT in early\u2010stage CLL.<\/jats:p>","DOI":"10.1111\/bjh.19052","type":"journal-article","created":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T06:09:31Z","timestamp":1692079771000},"page":"416-425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<i>XPO1<\/i> mutations identify early\u2010stage <scp>CLL<\/scp> characterized by shorter time to first treatment and enhanced <scp>BCR<\/scp> signalling"],"prefix":"10.1111","volume":"203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7393-1138","authenticated-orcid":false,"given":"Riccardo","family":"Moia","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine Universit\u00e0 del Piemonte Orientale  Novara 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