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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4771-4777
Dysregulation of CD95/CD95 Ligand-Apoptotic Pathway in
CD3+ Large Granular Lymphocyte Leukemia
Thierry Lamy,
Jin Hong Liu,
Terry H. Landowski,
William S. Dalton, and
Thomas P. Loughran Jr
From the H. Lee Moffitt Cancer Center and Research Institute, the
Veterans's Administration Hospital, and the Departments of Medicine,
Microbiology, Immunology, and Pharmacology, University of South Florida
Medical School, Tampa, FL.
CD95 (Fas)-induced apoptosis plays a critical role in the
elimination of activated lymphocytes and induction of peripheral tolerance. Defects in CD95/CD95L (Fas-Ligand)-apoptotic pathway have been recognized in autoimmune lymphoproliferative diseases (ALPS)
and lpr or gld mice and attributed to CD95 and CD95L
gene mutations, respectively. Large granular lymphocyte (LGL) leukemia is a chronic disease characterized by a proliferation of
antigen-activated cytotoxic T lymphocytes. Autoimmune features such as
hypergammaglobulinemia, rheumatoid factor, and circulating immune
complexes are common features in LGL leukemia and ALPS. Therefore, we
hypothesize that expansion of leukemic LGL may be secondary to a
defective CD95 apoptotic pathway. In this study, we investigated
expression of CD95 and CD95L in 11 patients with CD3+ LGL
leukemia and explored the apoptotic response to agonistic CD95
monoclonal antibody (MoAb). We found that leukemic LGL from each
patient expressed constitutively high levels of CD95/CD95L, similar to
those seen in normal activated T cells. However, cells from 9 of these
11 patients were totally resistant to anti-CD95-induced apoptosis.
Similarly, cells were resistant to anti-CD3-MoAb-triggered cell death.
Lack of anti-CD95-induced apoptosis was not due to mutations in the
CD95 antigen. Leukemic LGL were not intrinsically resistant to
CD95-dependent death, because LGL from all but 1 patient underwent
apoptosis after phytohemagglutinin/interleukin-2 activation. The
patient whose leukemic LGL were intrinsically resistant to CD95 had an
aggressive form of LGL leukemia that was resistant to combination
chemotherapy. These findings that leukemic LGL are resistant to
CD95-dependent apoptosis despite expressing high levels of CD95 are
similar to observations made in CD95L transgenic mice. These data
suggest that LGL leukemia may be a useful model of dysregulated
apoptosis causing human malignancy and autoimmune disease.
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