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Using two independent datasets (GSE249956 and GSE98206), differentially expressed genes (DEGs) were identified between ibrutinib-resistant and sensitive CLL samples. Protein\u2013protein interaction (PPI) network analysis revealed key hub genes related to resistance. Three common hub genes were shared across datasets: PDCD1, CD1C, and ITGB2. PDCD1, encoding the immune checkpoint protein PD-1, was selected for deeper investigation due to its important role in immune regulation and relevance in drug resistance. Post-transcriptional regulation of PDCD1 was explored by the construction of competing endogenous RNA (ceRNA) networks linking lncRNAs and miRNAs that may modulate PDCD1 expression, indicating complex upstream regulatory mechanisms. Transcription factors potentially regulating PDCD1 were identified, suggesting layers of transcriptional control contributing to ibrutinib resistance. Drug-gene interaction analysis showed that although PDCD1 is not directly targeted by ibrutinib. This implicates immune checkpoint blockade as a promising therapeutic strategy to overcome or complement resistance in CLL. In the broader context, PD-1 expression in CLL cells is linked to active proliferation and immune escape. Overall, our findings emphasize PDCD1\u2019s central role in ibrutinib resistance through immune checkpoint pathways and support the rationale for combining BTK inhibitors with immune checkpoint blockade therapies in resistant CLL cases.<\/jats:p>","DOI":"10.1007\/s10238-025-01942-2","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T02:38:13Z","timestamp":1763433493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PDCD1 as a targetable immune checkpoint hub: therapeutic insights for ibrutinib-resistant CLL management"],"prefix":"10.1007","volume":"26","author":[{"given":"Niloufar Sadat","family":"Kalaki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elham","family":"Karimi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kasra","family":"Allaei Rouzbahani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mozhgan","family":"Ahmadzadeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seyed Mohammad","family":"Akrami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"issue":"3","key":"1942_CR1","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1002\/ajh.27546","volume":"100","author":"M Hallek","year":"2025","unstructured":"Hallek M. 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