Mutation of CD95 (Fas/Apo-1) Gene in Adult T-Cell Leukemia Cells

Abstract

CD95 antigen (also known as Fas or Apo-1) and Fas ligand play key roles in apoptosis of cells of the immune system, function as effector molecules of cytotoxic T lymphocytes, and function in the elimination of activated lymphocytes during the downregulation of the immune response. The critical roles of the Fas-Fas ligand system in apoptosis suggest that its inactivation may be involved in malignant transformation. We analyzed the expression of Fas antigen on adult T-cell leukemia (ATL) cells by flow cytometry and found that Fas antigen expression was absent in a case of ATL and markedly decreased in another case among 47 cases examined. Apoptosis could not be induced in the Fas-negative ATL cells by antibody against Fas antigen. Sequencing of reverse transcription-polymerase chain reaction products of the Fas genes in the Fas negative cells showed two types of aberrant transcripts: one had a 5-bp deletion and a 1-bp insertion in exon 2, and the other transcript lacked exon 4. These mutations caused the premature termination of both alleles, resulting in the loss of expression of surface Fas antigen. These aberrant transcripts were not detected in a nonleukemic B-cell line from the same patient. An RNase protection assay of the Fas gene showed mutations in 2 additional cases with Fas-positive ATL cells of 35 cases examined: 1 case lacked exon 4 and the other was a silent mutation. In the Fas antigen-negative case, leukemic cells were resistant to anticancer drugs in vivo, indicating that the loss of expression of Fas antigen may be associated with a poor response to anticancer drugs. Indeed, Fas-negative ATL cells were resistant to adriamycin-induced apoptosis in vitro, which is consistent with the finding that ATL in this case was resistant to chemotherapy. These findings indicate that mutation of the Fas gene may be associated with the progression of ATL and with resistance to anticancer drugs.

Expression of CD95 in Acute Lymphocytic Leukemia (ALL) in Egyptian Children before and after Treatment

“…In the present study, results revealed that CD 95 % in blood of newly diagnosed ALL cases is significantly low when compared to controls while after treatment it showed significant increase. Consistent with our results, Tamiya et al [146] found defects in expression of Fas antigen on leukemia cells due to mutations in Fas genes of these cells. Moreover, Muschen et al [147] revealed that CD 95 /Fas (receptor-ligand system), is mutated and downregulated in lymphoid and solid tumors and loss of its function is associated with resistance to drug induced cell death.…”

Mutational analysis of Fas ligand gene in human non‐Hodgkin lymphoma

“…These germ‐line mutation models indicate that the key role of the Fas/FasL system is maintaining immune homeostasis. In agreement with these, human lymphoid malignancies were reported to have somatic mutations of the Fas gene (10–12).…”

Human T‐cell leukemia virus type‐I oncoprotein Tax inhibits Fas‐mediated apoptosis by inducing cellular FLIP through activation of NF‐κB

“…We speculate that Tax plays an important role for HTLV‐I‐infected cells to persistently proliferate and to escape Fas‐mediated apoptosis during the acute and carrier states, and then genetic and epigenetic changes accumulate in the host genome mediated by a mutator phenotype of Tax, which finally leads to Tax‐independent proliferation and survival of HTLV‐I‐infected T‐cells. Interestingly, 2–5% of ATL cells were reported to exhibit mutations in the Fas gene with associated Fas‐negative phenotype (Tamiya et al . 1998).…”