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Alliance"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:p>\n                    Splicing factor 3B subunit 1 (SF3B1) is involved in pre-mRNA branch site recognition and is the target of antitumor-splicing inhibitors. Mutations in\n                    <jats:italic>SF3B1<\/jats:italic>\n                    are observed in 15% of patients with chronic lymphocytic leukemia (CLL) and are associated with poor prognosis, but their pathogenic mechanisms remain poorly understood. Using deep RNA-sequencing data from 298 CLL tumor samples and isogenic\n                    <jats:italic>SF3B1<\/jats:italic>\n                    WT and K700E-mutated CLL cell lines, we characterize targets and pre-mRNA sequence features associated with the selection of cryptic 3\u2032 splice sites upon\n                    <jats:italic>SF3B1<\/jats:italic>\n                    mutation, including an event in the\n                    <jats:italic>MAP3K7<\/jats:italic>\n                    gene relevant for activation of NF-\u03baB signaling. Using the H3B-8800 splicing modulator, we show, for the first time in CLL, cytotoxic effects in vitro in primary CLL samples and in\n                    <jats:italic>SF3B1<\/jats:italic>\n                    -mutated isogenic CLL cell lines, accompanied by major splicing changes and delayed leukemic infiltration in a CLL xenotransplant mouse model. H3B-8800 displayed preferential lethality towards\n                    <jats:italic>SF3B1<\/jats:italic>\n                    -mutated cells and synergism with the BCL2 inhibitor venetoclax, supporting the potential use of SF3B1 inhibitors as a novel therapeutic strategy in CLL.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202301955","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T11:46:01Z","timestamp":1691667961000},"page":"e202301955","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["<i>SF3B1<\/i>\n                    mutation\u2013mediated sensitization to H3B-8800 splicing inhibitor in chronic lymphocytic 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