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180 Adult T-Cell Leukemia/Lymphoma in Japan: Reminiscences and Perspectives

Takatsuki, Kiyoshi; Matsuoka, Masao

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 75
doi: 10.1097/01.qai.0000397362.99286.a3

Adult T-cell leukemia/lymphoma (ATL) was first proposed as a distinct clinical entity based on observations in Japanese patients with T-cell leukemia. Observations typical of ATL include the presence of leukemic cells with multi-lobulated nuclei (flower cells), skin involvement, hypercalcemia, frequent complication with opportunistic infections, and an aggressive clinical course. Cell-mediated immunity is severely impaired in ATL patients, leading to immunodeficiency. Soon after the original report of ATL, Dr. Gallo and his colleagues found human T-cell leukemia virus type 1 (HTLV-1) in a Caribbean patient with T-cell malignancy. Thereafter, researchers have studied HTLV-1, and the mechanism by which this retrovirus causes ATL, extensively.

We found that an antisense transcript of HTLV-1, HTLV-1 bZIP factor (HBZ) was expressed in all ATL cases and promoted their proliferation. Analyses of proviral sequences of ATL cells and HTLV-1-infected cells in carriers showed frequent nonsense mutations in all viral genes except the HBZ gene. Almost all of the nonsense mutations arose from G-to-A mutations, and detailed analysis showed that these mutations were caused by APOBEC3G before retroviral integration. Since HBZ, alone among HTLV-1 genes, was unaffected, these data suggest that HBZ essential for both ATL cells and HTLV-1 infected cells in carriers.

Recent studies reported that more than half of ATL cases expressed FOXP3, indicating that ATL is a neoplastic disease of regulatory T-cells, at least in FOXP3 positive cases. We found that HBZ induced Foxp3 expression in naïve T-cells, and that regulatory T-cells increased in HBZ transgenic mice. T-cell lymphomas developed significantly more frequently in HBZ transgenic mice than in non-transgenic littermates. These data indicate that HBZ is responsible for the regulatory T-cell phenotype of ATL cells. Thus, studies on HBZ shed light on the mechanisms of HTLV-1-associated diseases.

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