{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:17:39Z","timestamp":1785421059029,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MetroHealth Foundation"},{"name":"National Cancer Institute","award":["R01CA248019"],"award-info":[{"award-number":["R01CA248019"]}]},{"name":"National Cancer Institute","award":["R01CA266256"],"award-info":[{"award-number":["R01CA266256"]}]},{"award":["R01CA248019"],"award-info":[{"award-number":["R01CA248019"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01CA266256"],"award-info":[{"award-number":["R01CA266256"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: The clinical efficacy of the BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) is significantly undermined by the frequent emergence of drug resistance, which precipitates disease progression and poor patient outcomes. However, the molecular landscape of this resistance remains insufficiently understood. Methods: To address this, we developed venetoclax-resistant AML cell models and utilized transcriptomic profiling integrated with comprehensive in vitro and in vivo functional assays. Results: Resistant cells demonstrated sustained proliferation even under the suppression of BCL-2, MCL-1, and key intrinsic apoptotic markers, including cleaved PARP and caspase-9, indicating a bypass mechanism independent of classical BCL-2 signaling. Compared to their sensitive counterparts, resistant Kasumi-1 (VENK) and MV4-11 (VENM) cells exhibit aggressive growth phenotypes in vitro and in vivo, characterized by larger, more numerous spheroids and colonies, alongside heightened tumorigenicity in murine models. Transcriptomic profiling and KEGG analysis identified the neuroactive ligand\u2013receptor interaction (NLRI) pathway as a significant signaling node shared between these resistant lines. While multiple NLRI-associated genes were altered, CHRNB4 was consistently and significantly downregulated in both VENK and VENM cells and tumors. Re-expression of CHRNB4 in resistant cells, a primary gain-of-function approach, significantly impaired colony formation, and tumor growth in vivo. Clinically, CHRNB4 downregulation correlates with shortened overall survival and diminished response to venetoclax. Conclusions: Our findings implicate the NLRI pathway in venetoclax resistance and identify CHRNB4 as a robust prognostic indicator and a promising therapeutic target for developing next-generation AML strategies.<\/jats:p>","DOI":"10.3390\/cancers18081187","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T09:49:44Z","timestamp":1775641784000},"page":"1187","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CHRNB4-Mediated Neuroactive Signaling Rewiring Drives Adaptive Resistance to BCL-2 Inhibition in Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"18","author":[{"given":"Hiroaki","family":"Koyama","sequence":"first","affiliation":[{"name":"Department of Medicine, The MetroHealth System, Case Western Reserve University, 2500 Metro Health Drive, Cleveland, OH 44109, USA"},{"name":"Department of Hematology, Tokyo Women\u2019s Medical University, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4308-2152","authenticated-orcid":false,"given":"Sachiko","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tokyo Women\u2019s Medical University, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Tse","sequence":"additional","affiliation":[{"name":"Department of Medicine, The MetroHealth System, Case Western Reserve University, 2500 Metro Health Drive, Cleveland, OH 44109, USA"},{"name":"Gene and Cell Therapy Institute (GCTI), The MetroHealth System, Case Western Reserve University, 2500 Metro Health Dr, Cleveland, OH 44109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9527-2102","authenticated-orcid":false,"given":"Sicheng","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Medicine, The MetroHealth System, Case Western Reserve University, 2500 Metro Health Drive, Cleveland, OH 44109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5347-8345","authenticated-orcid":false,"given":"Shujun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, The MetroHealth System, Case Western Reserve University, 2500 Metro Health Drive, Cleveland, OH 44109, USA"},{"name":"Gene and Cell Therapy Institute (GCTI), The MetroHealth System, Case Western Reserve University, 2500 Metro Health Dr, Cleveland, OH 44109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N. 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