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

Abstract

Chemoresistance poses a significant challenge to effective treatment and long-term remission in leukemia patients. Although many patients initially respond well to chemotherapy, they often relapse due to the emergence of drug-resistant cancer cells. This resistance can be either inherent or acquired, involving multiple mechanisms such as drug efflux, inhibition of apoptosis, and enhanced DNA repair. A key contributor to drug resistance is the ATP-binding cassette (ABC) transporter family, especially ABCB1 (P-gp), which actively effluxes chemotherapeutic drugs such as etoposide, doxorubicin, and vincristine from leukemia cells. Additionally, alterations in cellular signaling pathways, epigenetic changes, and interactions with the microenvironment further reduce drug sensitivity. Understanding the molecular basis of chemoresistance is essential for developing more effective and targeted therapies. Adult T-cell Leukemia/Lymphoma (ATLL), caused by the Human T-cell Leukemia Virus type 1 (HTLV-1), is a highly aggressive and chemoresistant form of leukemia. Despite the recent approval of several new agents, the prognosis for ATLL remains poor. Advances in chemotherapeutic regimens have not resolved the challenges of treating ATLL, due to its inherent and acquired resistance to multiple drugs. One of the primary mechanisms of chemoresistance in ATLL is the overexpression of drug efflux transporters, particularly multidrug resistance protein 1 (MDR-1), also known as P-glycoprotein (P-gp) or ABCB1. ABCB1 is an ATP-binding cassette (ABC) transporter that actively exports many chemotherapeutic drugs from cells, thereby reducing intracellular drug accumulation. In this study, we compare the expression of ABC transporter genes in CD8+-depleted PBMCs from HTLV-1 asymptomatic carriers and patients with acute ATLL. We show that ABCB1 is significantly upregulated in acute ATLL. Our results further demonstrate that the viral protein Tax decreases ABCB1 expression in HuT78 and JPX9 cell lines. Using Valproic acid to reactivate Tax expression in CD8+-depleted PBMCs from acute ATLL patients, we confirm that Tax lowers ABCB1 expression and restores ATLL sensitivity to chemotherapeutic agents such as etoposide and doxorubicin. Our findings suggest that a "Tax-based-shock and kill" approach could potentially overcome chemoresistance in ATLL.