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Department of Laboratory Medicine, and the Department of Bacteriology, Nagasaki University School of Medicine, Nagasaki 852-8102, Japan; and the || Department of Laboratory Chemotherapy, Aichi Cancer Center, Aichi 464-0021, Japan
Fas antigen (Apo-1/CD95) is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor receptor superfamily. Adult T cell leukemia (ATL) cells express Fas antigen and show apoptosis after treatment with an anti-Fas monoclonal antibody. We established the ATL cell line KOB, which showed resistance to Fas-mediated apoptosis, and found that KOB expressed two forms of Fas mRNA, the normal form and a truncated form. The truncated transcript lacked 20 base pairs at exon 9, resulting in a frame shift and the generation of a premature stop codon at amino acid 239. The same mutation was detected in primary ascitic cells and peripheral blood cells. The mutation was not detected in lymph node cells, however, although all of the primary ATL cells were of the same clonal origin. A retroviral-mediated gene transfer of the truncated Fas to Jurkat cells rendered the cells resistant to Fas-mediated apoptosis, suggesting a dominant negative interference mechanism. These results indicate that an ATL subclone acquires a Fas mutation in the lymph nodes, enabling the subclone to escape from apoptosis mediated by the Fas/Fas ligand system and proliferate in the body. Mutation of the Fas gene may be one of the mechanisms underlying the progression of ATL.
Key Words: human T lymphotropic virus type I • adult T cell leukemia • apoptosis • death domain • CD95
Abbreviations used: ALPS, autoimmune lymphoproliferative syndrome; ATL, adult T cell leukemia; HTLV-I, human T lymphotrophic virus type I; LDH, lactic dehydrogenase; nt, nucleotide; RT, reverse transcriptase.
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