Analysis of p53 inactivation in a human T-cell leukemia virus type 1 Tax transgenic mouse model

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL). The HTLV-1 Tax protein has been strongly linked to oncogenesis and is considered to be the transforming protein of t his virus. A Tax transgenic mouse model was utilized to study the contribut ion of p53 inactivation to Tax-mediated tumorigenesis. These mice develop p rimary, peripheral tumors consisting of large granular lymphocytic (LGL) ce lls, which also infiltrate the lymph nodes, bone marrow, spleen, liver, and lungs. Primary Tax-induced tumors and tumor-derived cell lines exhibited f unctional inactivation of the p53 apoptotic pathway; such tumors and tumor cell lines were resistant to an apoptosis-inducing stimulus. In contrast, p 53 mutations in tumors were found to be associated with secondary organ inf iltration. Three of four identified mutations inhibited transactivation and apoptosis induction activities in vitro. Furthermore, experiments which in volved mating Tax transgenic mice with p53-deficient mire demonstrated mini mal acceleration in initial tumor formation, but significantly accelerated disease progression and death in mice heterozygous for p53, These studies s uggest that functional inactivation of p53 by HTLV-1 Tax, whether by mutati on or another mechanism, is not critical for initial tumor formation, but c ontributes to late-stage tumor progression.