Bcl-X-L is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLLsamples

Human T lymphotropic virus type I (HTLV-I) is the etiological agent of adul t T-cell lymphocytic leukemia (ATLL), whereas HTLV-II has not been associat ed with hematopoietic malignancies. The control of apoptotic pathways has e merged as a critical step in the develop ment of many cancer types. As a re sult, the underlying mechanism of long-term survival of HTLV-I and HTLV-II was studied in infected T cells in vitro and in ex vivo ATLL samples. Resul ts Indicate that HTLV-I- and HTLV-II-infected T cells in vitro express high levels of the antiapoptotic protein Eel compared with other human leukemic T cell lines or uninfected peripheral blood mononuclear cells. The levels of proapoptotic proteins Bax, BAD, and Bak were not significantly altered. HTLV-I and HTLV-II viral transactivators, Tax1 and Tax2, are known to incre ase expression of cellular genes. These proteins were tested for increased transcription from the human Bcl2 and Bcl-X-L promoters. Whereas no effect was observed on the Bcl2 promoter, both Tax1 and Tax2 increased transcripti on of the Bcl-X-L promoter in T cells, although Taxi appeared to be more ef ficient than Tax2. The biological significance of these observations was va lidated by the finding of an increased expression of Bcl-X-L in ex vivo ATL L cells, especially from patients unresponsive to various chemotherapy regi mens. Altogether, these data suggest that overexpression of Bcl-X-L in vivo may be in part responsible for the resistance of ATLL cells to chemotherap y. In addition, inefficient activation of the Bcl-X-L promoter by Tax2 may result in a shorter survival time of HTLV-II-infected cells in vivo and a d iminished risk of leukemia development. (Blood. 2000;96:275-281) (C) 2000 b y The American Society of Hematology.