{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T11:04:55Z","timestamp":1777892695616,"version":"3.51.4"},"reference-count":60,"publisher":"American Society of Hematology","issue":"26","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,25]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>The transcription factor lymphoid enhancer-binding factor 1 (LEF1) is aberrantly expressed across all subtypes and stages of chronic lymphocytic leukemia (CLL), yet the molecular mechanisms underlying its contribution to CLL pathogenesis remain poorly defined. Here, we conducted a comprehensive mechanistic dissection of LEF1 function in CLL using extensive functional analyses of patient-derived samples. We identified that, although LEF1 messenger RNA levels remain stable, patients with clinically aggressive disease show elevated LEF1 protein levels due to enhanced protein stability. LEF1 protein abundance is selectively modulated by lymph node\u2013derived stimuli, including T-cell interactions and B-cell receptor signaling. Importantly, we uncovered a dual, context-dependent role for LEF1 that is determined by its protein levels. Low LEF1 protein, characteristic of indolent disease, supports B-cell activation, whereas increased protein abundance in aggressive disease promotes proliferation through the binding and induction of cell cycle and metabolic gene networks. We further showed that LEF1 exon 6 skipping is enriched in proliferative and aggressive CLL. Both in vitro and in vivo experiments revealed that LEF1-driven proliferation is mediated by these short, alternative spliced isoforms. Although all LEF1 isoforms bind to a core set of proliferation- and activation-related genes, they induce distinct transcriptional programs; full-length LEF1 promotes a quiescence gene signature and limits leukemic growth, whereas exon 6-skipping isoforms drive proliferation. Our findings establish LEF1 as an oncogenic transcription factor in CLL whose biological and clinical effects are modulated posttranscriptionally by both protein abundance and isoform composition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025030129","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T21:52:43Z","timestamp":1758577963000},"page":"3213-3227","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":2,"title":["Increased LEF1 protein levels and isoform switching drive cell proliferation in chronic lymphocytic leukemia"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3850-3231","authenticated-orcid":false,"given":"Judith","family":"Mateos-Jaimez","sequence":"first","affiliation":[{"name":"1Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain"},{"name":"2Centro de Investigaci\u00f3n Biom\u00e9dica en 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Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4910-5394","authenticated-orcid":false,"given":"Vicente","family":"Chapaprieta","sequence":"additional","affiliation":[{"name":"1Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, Spain"},{"name":"2Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7087-7057","authenticated-orcid":false,"given":"V\u00edctor","family":"Jim\u00e9nez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"1Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer, Barcelona, 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