{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:16:28Z","timestamp":1788434188135,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Background\/Objectives: Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy in which B-cell receptor signaling, microenvironmental interactions, genomic lesions, and epigenetic deregulation cooperate to shape disease behavior. The imprinted DLK1-DIO3 locus at chromosome 14q32 contains the largest human miRNA cluster and has been implicated in cancer-related regulatory networks; however, its contribution to CLL remains incompletely defined. Methods: In the present study, we investigated the potential involvement of DLK1-DIO3 miRNAs in CLL biology by integrating public transcriptomic datasets with miRNA-centered pathway analysis. GSE70830 was used as a discovery dataset and GSE66117 as a supportive validation cohort to identify genes consistently downregulated in CLL compared with normal B cells. Results: The analyses identified 1236 and 2145 downregulated genes, respectively, and their intersection yielded a 345-gene consensus set. The overlap was significantly greater than expected by chance (odds ratio 2.33; p = 1.55 \u00d7 10\u221231). This set was used as gene-filter input for DIANA-miRPath v3.0 analysis of the DLK1-DIO3 miRNA cluster, identifying eight KEGG pathways mainly involving B-cell receptor\/NF-\u03baB signaling, cell adhesion, leukocyte transendothelial migration, and glycan-related processes. DIANA-miRPath v4.0 provided pathway-centered refinement. GSE216258 miRNA analysis did not show generalized locus-wide upregulation, while a GSE12366 sensitivity analysis showed that 32 of the 345 genes overlapped the strongest na\u00efve-memory B-cell differentiation signatures. The absence of uniform locus-wide upregulation suggests that these data do not establish a direct link between DLK1-DIO3 activation and generalized repression of the 345-gene set. Future studies are needed to identify gene- and pathway-specific effects. Conclusions: Overall, our findings support an association between DLK1-DIO3 miRNA target\/pathway annotations and CLL-relevant transcriptional programs, providing a hypothesis-generating framework that warrants further experimental validation.<\/jats:p>","DOI":"10.3390\/diseases14090320","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:10:33Z","timestamp":1788430233000},"page":"320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic and miRNA\u2013Target Pathway Analysis of the DLK1-DIO3 Imprinted microRNA Cluster in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7700-7003","authenticated-orcid":false,"given":"Georgios S.","family":"Markopoulos","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1764-8906","authenticated-orcid":false,"given":"Yannis V.","family":"Simos","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7032-1630","authenticated-orcid":false,"given":"Konstantinos I.","family":"Tsamis","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Lampros","family":"Lakkas","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4408-5646","authenticated-orcid":false,"given":"Eleftheria","family":"Hatzimichael","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Eleni","family":"Kapsali","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Dimitrios","family":"Peschos","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Leonidas","family":"Benetatos","sequence":"additional","affiliation":[{"name":"Department of Hematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/ajh.27546","article-title":"Chronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy","volume":"100","author":"Hallek","year":"2025","journal-title":"Am. 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