LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway

Adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), is resistant to treatment. In this study, we examined the effects of a new inhibitor of deacetylase enzymes, LBH589, on ATLL cells. LBH589 effectively induced apoptosis in ATLL-related cell lines and primary ATLL cells and reduced the size of tumors inoculated in SCID mice. Analyses, including with a DNA microarray, revealed that neither death receptors nor p53 pathways contributed to the apoptosis. Instead, LBH589 activated an intrinsic pathway through the activation of caspase-2. Furthermore, small interfering RNA experiments targeting caspase-2, caspase-9, RAIDD, p53-induced protein with a death domain (PIDD) and RIPK1 (RIP) indicated that activation of RAIDD is crucial and an event initiating this pathway. In addition, LBH589 caused a marked decrease in levels of factors involved in ATLL cell proliferation and invasion such as CCR4, IL-2R and HTLV-1 HBZ-SI, a spliced form of the HTLV-1 basic zipper factor HBZ. In conclusion, we showed that LBH589 is a strong inducer of apoptosis in ATLL cells and uncovered a novel apoptotic pathway initiated by activation of RAIDD

Newly Emerging Therapies Targeting Viral-Related Lymphomas

Gamma-(γ)-herpes virus lymphomas comprise a heterogenous group of B-cell and T-cell neoplasms most commonly associated with Epstein Barr virus (EBV) and rarely human herpes virus-8 (HHV-8) infection. Adult T-cell leukemia/lymphoma (ATLL) is a unique disease entity caused by the human T-cell lymphotrophic virus, type 1 (HTLV-I), the only retrovirus known to cause cancer in humans. Viral lymphomas behave aggressively and disproportionally affect immunocompromised individuals and those living in underdeveloped regions. These diseases are often difficult to treat with conventional approaches. Despite recent advancements using cytotoxic, lymphoma-specific, and adoptive therapies, the long-term outcome of patients with γ-herpesvirus lymphomas occurring in severely immunocompromised patients and ATLL continues to be poor. Lytic-inducing therapies targeting NF-κB, and viral and tumor cell epigenetic mechanisms afford the advantage of exploiting the intrinsic presence of oncogenic viruses to eradicate infected tumor cells. In this review, viral-related lymphomas and newly emerging clinical approaches targeting viral latency are discussed