The State of the Art in the Pathogenesis of ATL and New Potential Targets Associated with HTLV-1 and ATL

Abstract

Almost 30 years have passed since adult T-cell leukemia (ATL) was identified as a new disease entity in Japan. During this period, its causative agent, human T-cell leukemia virus (HTLV-1), was discovered, and a crucial role of the viral product Tax in ATL leukemogenesis was demonstrated. Recently, another HTLV-1 product, HBZ, which is encoded on the negative strand, was found, and it has now become a subject of intensive research because of its possible activity in cell proliferation. It is, however, impossible to elucidate the whole process of ATL leukemogenesis by studying only HTLV-1, and aberrations of cellular genes such as tumor suppressor genes are also profoundly involved in the later stages of ATL development. In contrast with the progress in the understanding of ATL pathogenesis, more progress in developing therapy for ATL is needed, and there has been only slight improvement in the prognosis. Recently, unique therapeutic approaches targeting molecules and/or mechanisms involved in the pathogenesis have been explored, and some of them produced encouraging results that might lead to breakthrough therapies. One of these approaches, the use of monoclonal antibody against chemokine receptor CCR4, is now ongoing as a multicenter clinical trial in Japan. Here we review the state of the art regarding our understanding of ATL leukemogenesis and new potential molecular targets in ATL therapy.

KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

“…Several studies has made efforts to work out the pathogenesis of ATL [33,34], however, it remains one of the most lethal malignancy due to ineffective therapy.…”

A new high-performance liquid chromatography method determines low production of 9-β-D-arabinofuranosylguanine triphosphate, an active metabolite of nelarabine, in adult T-cell leukemia cells

“…ATL is an aggressive malignancy of mature activated CD4 + T-cells that is associated with HTLV-1 infection (13)(14)(15). ATL develops in 1 to 3% of infected individuals after more than two decades of viral persistence.…”

“…Determination of intracellular ara-GTP concentrations would help determine the potential therapeutic efficacy of nelarabine against other malignancies that are refractory to conventional chemotherapy. One such T-cell malignancy is adult T-cell leukemia (ATL) (13)(14)(15). ATL is associated with human T-cell leukemia virus type 1 (HTLV-1) infection.…”

Fully Human Antagonistic Antibodies against CCR4 Potently Inhibit Cell Signaling and Chemotaxis

“…The CC-chemokine receptor 4 (CCR4) is also highly expressed on tumor cells of T-cell derived variants of non-Hodgkin’s lymphoma (NHL), such as adult T-cell leukemia/lymphoma (ATLL) [13], [14], cutaneous T-cell lymphoma (CTCL) [15], [16], and other kinds of malignancies belonging to the heterogeneous group of peripheral T-cell lymphoma (PTCL) [17]. In Western countries, PTCL accounts for 15–20% of aggressive lymphomas and 5–10% of all NHL [18].…”