CONSTITUTIVELY ACTIVATED JNK IS ASSOCIATED WITH HTLV-1 MEDIATED TUMORIGENESIS

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukiemia (ATL) and HTLV-1 associated myelopathy, also ca lled tropical spastic paraparesis (HAM/TSP). Both clinical and in vitr o evidence have demonstrated that the virus or its transactivator Tax, are transforming, However, transformation appears to require addition al, as yet poorly characterized, genetic changes in infected cells, JN K is a recently characterized member of the MAP kinase family. Its sig naling cascade is distinct from other members and has been demonstrate d to play an important role in T-cell activation, at least partially t hrough its downstream targets, c-jun and ATF-2. Here we demonstrate co nstitutive activation of the JNK cascade in human lymphocytes transfor med in vitro by HTLV-1 and also in Tax transformed murine fibroblasts. Such activation is not induced by Tax expression alone, and occurs on ly when infected lymphocytes become IL-2 independent or immortalized. Constitutive JNK activation was also found in leukocytes isolated from ATL patients. The acquisition of constitutive JNK activation may repr esent an important later event in HTLV-1 tumorigenesis.