Bcl-X(L) is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLL samples.
Human T lymphotropic virus type I (HTLV-I) is the etiological agent of adult T-cell lymphocytic leukemia (ATLL), whereas HTLV-II has not been associated with hematopoietic malignancies. The control of apoptotic pathways has emerged as a critical step in the development of many cancer types. As a result, 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. Results indicate that HTLV-I- and HTLV-II-infected T cells in vitro express high levels of the antiapoptotic protein Bcl 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 increase 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 transcription of the Bcl-X(L) promoter in T cells, although Tax1 appeared to be more efficient than Tax2. The biological significance of these observations was validated by the finding of an increased expression of Bcl-X(L) in ex vivo ATLL cells, especially from patients unresponsive to various chemotherapy regimens. Altogether, these data suggest that overexpression of Bcl-X(L )in vivo( )may be in part responsible for the resistance of ATLL cells to chemotherapy. 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 diminished risk of leukemia development.
Nicot
C
C
Basic Research Laboratory Division of Basic Sciences, Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. cbeben@helix.nih.gov
Mahieux
R
R
Takemoto
S
S
Franchini
G
G
D000328:Adult; D002461:Cell Line, Transformed; D016356:Gene Products, tax / Q000235:genetics; D019254:Genes, bcl-2; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000502:physiology*; D015367:Human T-lymphotropic virus 2 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000097:blood* / Q000276:immunology; D007958:Leukocyte Count; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis; D012016:Reference Values; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology* / Q000821:virology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D016356:Gene Products, tax; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein