BCL-2 family dysregulation in HTLV-1 and BLV pathogenesis and its implications for leukemogenesis and therapy.

The B-cell Lymphoma 2 (BCL-2) family of proteins plays a fundamental role in maintaining the balance between cell survival and apoptosis, processes that are frequently manipulated by oncogenic viruses. 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-Associated X Protein ( BAX ), BIM (BCL-2-Interacting 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-κB (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-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) and BLV-associated leukosis.