LYMPHOID NEOPLASIA

Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/ lymphoma (ATL). Although the pathogen-esis of these disorders is poorly under-stood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through in-duction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypoth-esis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4 T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immor-talization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as im-portant in T-cell survival. Immortalized cells exhibited a CD4CD25CD3 pheno-type commonly observed in ATL. Engraft-ment of activated LTR-Tax CD4 T cells into NOD/Shi-scid/IL-2R null mice re-sulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax, CD4 lymphocytes. We suggest that im-mune activation of infected CD4 T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis ofATLin HTLV-1–infected indi-viduals. (Blood. 2010;116(16):2994-3003