Mutation analysis of CD95 (APO‐1/Fas) in childhood B‐lineage acute lymphoblastic leukaemia

Abstract

Summary. The CD95 system plays an important role in lymphocyte homeostasis, has been implicated in the development of lymphoid malignancies, exerts a tumour suppressor function, and contributes to drug-induced cytotoxicity. We hypothesized that mutations of CD95 may occur in childhood B-lineage acute lymphoblastic leukaemia (ALL), a disease known for its constitutive resistance towards CD95-mediated apoptosis. We investigated 32 primary Blineage ALL of childhood and five B-lineage ALL cell lines. All primary leukaemias expressed CD95 and bcl-2 to a variable degree. Most of the leukaemias were resistant towards CD95-mediated apoptosis. However, using SSCP analysis, no mutations in the coding and proximal promoter region could be detected. We conclude that the resistance towards CD95-mediated apoptosis observed in most de novo Blineage ALL is not caused by mutations of the CD95 death receptor.Keywords: CD95 (APO-1/Fas), apoptosis, B-lineage acute lymphoblastic leukaemia, mutation.The APO-1 (CD95/Fas) system is pivotal in maintaining both B-and T-cell equilibrium and plays an important role in growth control of other cell types (reviewed by Nagata, 1997). Many cell types, both normal and malignant, express CD95 including cells of B-lineage (Leithäuser et

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

“…Tumor cells can be resistant to death receptor-induced apoptosis, either due to the expression of decoy receptors or the inactivation or loss of the targeted receptor or distal signaling cascades. Mutations in CD95 have been described in T-lineage acute leukemias 122,123 or Burkitt lymphoma and loss of caspase-8 expression was found in childhood neuroblastomas. 124 In addition, clonal variability in CD95/Fas expression has been demonstrated to be a major determinant in the development of resistance against death signaling via the CD95/Fas receptor.…”

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

“…25 Fas gene mutations that characterize some congenital autoimmune lymphoproliferative syndromes (ALPS) inhibit Fasmediated apoptosis by a dominant-negative mechanism. 32 Several Fas gene mutations have also been described in lymphoid malignancies, including myelomas, 33 T cell lymphoblastic leukemias 34 and HTLV-I-related adult T cell leukemias (ATL). 35 In this latter disease, mutated Fas was also demonstrated to behave as a dominant-negative mutant, 36 which could account for the chemoresistance of ATL.…”

“…Tumor cells have developed multiple mechanisms to resist to Fas-mediated cell death including reduction or loss of Fas from the leukemic cell surface, 135 mutation of the cytoplasmic domain of Fas, [32][33][34][35] secretion of the soluble form of Fas, overexpression of anti-apoptotic proteins of the Bcl-2 family 136 and overexpression of the previously described inhibitor known as c-FLIP. 77,137 This latter protein is structurally related to procaspase-8 but lacks a catalytic active site and the residues that form the substrate binding pocket and competitively interacts with FADD, caspase-8 and possibly caspase-10.…”

Clinical and oncological significance of aberrant Fas (APO-1/CD95) isoform expression in adult T-cell leukemia

“…In some cases, although there was mFas lacking the intracytoplasmic signaling domain, no cell death could be induced through the Fas-signal system (33). Such cases, however, are rare among the patients examined for Fas mutation (15)(16)(17)(18) so that the remaining majority of cases should be considered to have normal Fas genes. Now, there have been two reports about Fas mutations in ATL; one by Tamiya et a1.…”