Valproate reactivates HTLV-1 tax and reduces ABCB1/MDR1 expression in PBMCs derived from ATLL patients.

Chemoresistance remains a major obstacle to effective treatment and durable remission in leukemia patients. Although initial responses to chemotherapy are often favorable, relapse frequently occurs due to the emergence of drug-resistant malignant clones. Resistance mechanisms may be intrinsic or acquired and involve drug efflux, impaired apoptosis, enhanced DNA repair, epigenetic alterations, dysregulated signaling pathways, and microenvironmental interactions. A central mediator of multidrug resistance is the ATP-binding cassette (ABC) transporter family, particularly ABCB1 (also known as P-glycoprotein or MDR-1), which actively exports chemotherapeutic agents such as etoposide, doxorubicin, and vincristine, thereby reducing intracellular drug accumulation. Adult T-cell Leukemia/Lymphoma (ATLL), an aggressive malignancy caused by Human T-cell Leukemia Virus type 1 (HTLV-1), is characterized by poor prognosis and marked resistance to chemotherapy. Despite the recent approval of novel therapeutic agents, treatment outcomes remain unsatisfactory, largely due to both inherent and acquired chemoresistance. Overexpression of ABCB1 has been identified as a key mechanism contributing to multidrug resistance in ATLL. We compared the expression profiles of ABC transporter genes in CD8⁺-depleted peripheral blood mononuclear cells (PBMCs) from HTLV-1 asymptomatic carriers and patients with acute ATLL. To investigate the role of the viral transactivator Tax in regulating ABCB1 expression, we used HuT78 and JPX9 T-cell lines. Furthermore, Tax expression was reactivated in CD8⁺-depleted PBMCs from acute ATLL patients using valproic acid, and subsequent changes in ABCB1 expression and chemosensitivity to etoposide and doxorubicin were assessed. We found that ABCB1 expression was significantly upregulated in CD8⁺-depleted PBMCs from patients with acute ATLL compared to asymptomatic HTLV-1 carriers. In contrast, expression of the viral protein Tax in HuT78 and JPX9 cell lines resulted in decreased ABCB1 levels. Reactivation of Tax expression using valproic acid in primary ATLL samples confirmed that Tax downregulates ABCB1 expression. Importantly, Tax reactivation restored sensitivity of ATLL cells to chemotherapeutic agents, including etoposide and doxorubicin. Our findings identify ABCB1 overexpression as a major contributor to chemoresistance in acute ATLL and demonstrate that the viral protein Tax negatively regulates ABCB1 expression. These results suggest that reactivation of Tax may reduce drug efflux capacity and restore chemosensitivity in resistant ATLL cells. Collectively, this study provides a rationale for exploring a "Tax-based shock-andkill" strategy as a potential therapeutic approach to overcome chemoresistance in ATLL.