Abstract
Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy with poor prognosis that is incurable by conventional drugs. Histone deacetylase (HDAC) inhibitors (HDIs) are broadly active anti-neoplastic agents that can be cautiously exploited in the treatment of ATLL. The HTLV-I provirus is clonally integrated in virtually all ATLL cells. The HTLV-I 5'LTR promoter is trans -activated by the viral protein Tax through binding of CREB and p300/CBP. Tax binding enhances p300/CBP histone acetyl transferase (HAT) activity resulting in histone acetylation, chromatin unwinding, and transcription of the viral genome. HAT activity is countered by HDACs, and also by the viral-encoded protein HTLV-I bZip factor (HBZ), which is transcribed from the negative proviral strand at the 3' end. The 5' LTR is often mutated or deleted in ATLL cells thus HBZ is the only viral gene consistently expressed in ATLL. We hypothesized that HDAC inhibitors, which can be potent anti-neoplastic drugs, would reactivate HTLV-I in ATLL tumors containing intact provirus, thus killing virus-infected cells and provoking an immune response in vivo. Supporting this notion, adding the old generation HDI valproic acid (VPA) to AZT/IFNa in one subject suffering from aggressive acute-type ATLL resulted in HTLV-I proviral load reduction, followed by a complete molecular and prolonged clinical remission that lasted several years. We recently tested other more potent HDIs on primary ATLL cells and low-passage cell lines, which are rare and difficult to establish. In general, HDIs induced dose-dependent Tax expression and apoptosis in ATLL cells. Belinostat, a pan HDI, caused H3 acetylation, blocked HBZ protein expression, and induced Tax protein expression in ATLL cells resulting in concomitant apoptosis. ATLL cells exhibit high constitutive expression of nuclear factor kappa B (NF-kB), which is known to be activated by Tax and to play a major role in HTLV-I mediated T-cell transformation and ATLL development. Paradoxically, while belinostat induced Tax, it also inhibited NF-kB nuclear activity resulting in apoptosis. Further, adding AZT to belinostat augmented ATLL cell death. By contrast, IFNα diminished apoptosis induced by belinostat in freshly isolated ATLL cells from some of our patients. Based on these preclinical data, we have developed a clinical trial using belinostat in combination with AZT as consolidation therapy for ATLL. Our primary goal using this approach is to eradicate residual ATLL cells and HTLV-I infected reservoirs that normally persist regardless of treatment.
Disclosures
No relevant conflicts of interest to declare.
Adult T-cell leukemia cells over-express the multidrug-resistance-protein (MRP) and lung-resistance-protein (LRP) genes