Viral, genetic, and immune factors in the oncogenesis of adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4 + T cells induced by human T-cell leukemia virus type I (HTLV-1). HTLV-1 maintains life-long infection in the human host by clonal proliferation of infected cells and cell-to-cell spread of the virus. Two viral genes, tax and HTLV-1 bZIP factor (HBZ), promote expansion of infected cells through the important roles they play in acceleration of cell proliferation and protection from cell death. Long-term survival of infected clones in vivo causes genetic mutations and aberrant epigenetic changes to accumulate in host genes, resulting in the emergence of an ATL clone. Recent advances in sequencing technology have revealed the broad picture of genetic and transcriptional abnormalities in ATL cells. ATL cells have hyper-proliferative and anti-apoptotic signatures like those observed in other malignancies, but also notably have traits related to immune evasion. ATL cells exhibit a regulatory T-cell-like immuno-phenotype due to both the function of HBZ and mutation of several host genes, such as CCR4 and CIC. These findings suggest that immune evasion is a critical step in the oncogenesis of ATL, and thus novel therapies that activate anti-ATL/HTLV-1 immunity may be effective in the treatment and prevention of ATL.