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Ramos lab

Targeting pathogenesis of HTLV-1 associated adult T-cell leukemia-lymphoma

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Investigator / Contact Person Juan Carlos Ramos

Research

Adult T-cell leukemia-lymphoma (ATLL) is an aggressive and fatal malignancy caused by the human T-cell leukemia virus, type 1 (HTLV-1). The retrovirus is primarily transmitted sexually or via breastfeeding. At least 10 million people worldwide may be infected with HTLV-1. In the U.S., HTLV-1 infection and ATLL usually occur disparately in marginalized U.S. sub populations comprised of Afro-Caribbean descendants. HTLV- 1 and related diseases represent a public health concern in South Florida and New York City, which are the U.S. areas most populated by immigrants from the Caribbean islands, and their descendants. Between 2-5% of HTLV- 1 infected individuals develop ATLL during their lifetime. The aggressive and most common ATLL variants have a median survival of 6-10 months, and cannot be cured by conventional chemotherapy. HTLV-1 infection is challenging to treat because it establishes latency in host T-cells, which undergo clonal expansion and genetic instability over a lifetime. The HTLV-1 provirus promoter is under transcriptional control of histone deacetylases (HDACs) at the 5’ LTR, and by HTLV-1 basic leucine zipper factor (HBZ), which is constitutively transcribed from the negative strand at the 3’ end of the provirus. The HTLV-1 promoter is transactivated by its own viral protein, Tax, which binds CREB and recruits p300/CBP to the 5’ LTR. Given these mechanisms of regulation, HDAC inhibitors, which are widely used anti-neoplastic agents, promote the activation of HTLV-1 from latency. We recently conducted a pilot trial using the old generation HDAC inhibitor valproic acid (VPA) combined sequentially with AZT/interferon-α (IFNα) during maintenance therapy in patients with ATLL. We hypothesized that VPA would reactivate HTLV-1 thus provoking an immune response against minimal residual ATLL cells, which normally persist during AZT/IFNα therapy alone. Supporting this notion, adding VPA resulted in reduction of HTLV-1 proviral load in treated subjects, and induced molecular remission in one subject. Subsequent studies demonstrated that the HDAC inhibitors (VPA, and belinostat) completely abrogated HBZ and activated Tax followed by apoptosis. Combining AZT with belinostat augmented ATLL cell death. Based on these concepts, our group developed a pilot trial using belinostat as consolidation therapy with AZT-based regimen. The objectives of this study are to determine whether adding belinostat to AZT-based therapy eradicates ATLL, to investigate whether belinostat disrupts HTLV-1 latency thus provoking a cytotoxic T-cell response in vivo, and to elucidate the molecular basis of belinostat and HDAC inhibitors in ATLL using our pre-clinical models.