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This review explores the contribution of BCL-2 family members to the pathogenesis of deltaretroviruses, with emphasis on Human T-cell Leukemia Virus type 1 (HTLV-1) and Bovine Leukemia Virus (BLV). Both viruses employ viral oncoproteins such as Tax and HBZ (HTLV-1) or their BLV homologs to upregulate anti-apoptotic proteins, including BCL-2, BCL-xL (B-cell Lymphoma-extra Large), MCL-1 (Myeloid Cell Leukemia 1), and Bfl-1, while suppressing pro-apoptotic counterparts such as BCL-2\u2013Associated X Protein ( BAX ), BIM (BCL-2\u2013Interacting Mediator of Cell Death), and BID (BH3-Interacting Domain Death Agonist). This dysregulation prolongs the survival of infected lymphocytes and promotes clonal expansion, genomic instability, and malignant transformation. Importantly, studies demonstrate that BLV and HTLV-1 infection induce resistance to programmed cell death in lymphoid and even non-lymphoid cells, highlighting apoptosis evasion as a central mechanism of viral persistence. Therapeutically, BCL-2 family inhibition has shown promise in sensitizing transformed cells to apoptosis. Small-molecule inhibitors such as ABT-737 and Navitoclax, kinase inhibitors targeting NF-\u03baB (Nuclear Factor kappa-light-chain-enhancer of Activated B Cells) and JAK\/STAT (Janus Kinase\/Signal Transducer and Activator of Transcription) pathways, and natural compounds including fucoxanthin, peridinin, and thymoquinone have demonstrated the ability to overcome apoptosis resistance in preclinical models. Recent strategies combining MCL-1 inhibitors with antiretroviral therapy or immune checkpoint blockade further highlight the translational potential of targeting BCL-2 pathways. Collectively, the evidence positions the BCL-2 family as a critical determinant of deltaretroviral persistence and leukemogenesis, and as a promising therapeutic axis for the development of novel treatments for HTLV-1\u2013Associated Myelopathy\/Tropical Spastic Paraparesis (HAM\/TSP) and BLV-associated leukosis.<\/jats:p>","DOI":"10.1007\/s11033-025-11216-5","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T13:08:14Z","timestamp":1762520894000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["BCL-2 family dysregulation in HTLV-1 and BLV pathogenesis and its implications for leukemogenesis and therapy"],"prefix":"10.1007","volume":"53","author":[{"given":"Mohammad Mehdi","family":"Akbarin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Farjami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Eduardo","family":"Acevedo-Jim\u00e9nez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia Rodr\u00edguez","family":"Murillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor David","family":"Gonz\u00e1lez-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucero","family":"de Mar\u00eda Avila-De la Vega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela Autran","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harim Jahaziel Nava","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1682-8104","authenticated-orcid":false,"given":"Hugo Ram\u00edrez","family":"\u00c1lvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"11216_CR1","doi-asserted-by":"publisher","unstructured":"Palabiyik AA (2025) The role of Bcl\u20132 in controlling the transition between autophagy and apoptosis (Review). 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