Epigenetic Targeting of Afro-Caribbean Variant of HTLV-1 Related Adult T-cell Leukemia-lymphoma

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PROJECT SUMMARY Adult T-cell leukemia-lymphoma (ATL) is an aggressive and fatal malignancy caused by the human T- lymphotropic 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. ATL occurs disparately in the U.S. affecting mainly African descendants from the Caribbean islands, such as Haiti and Jamaica, where HTLV-1 is endemic. 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 ATL during their lifetime. The aggressive and most common ATL 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 ATL. We hypothesized that VPA would reactivate HTLV-1 thus provoking an immune response against minimal residual circulating ATL 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. We recently observed that HDAC inhibitors (VPA, and belinostat) completely abrogate HBZ and activate Tax followed by apoptosis. Combining AZT with belinostat augmented ATL cell death. Based on these concepts, we proposed 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 ATL in human subjects, 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 ATL using our pre-clinical models. We are poised to carry out this high-impact proposal that promises to help advance the treatment of ATL.