We report here that anticancer drugs such as doxorubicin lead to induction of the CD95 (APO‐1/Fas) system of apoptosis and the cellular stress pathway which includes JNK/SAPKs. Ceramide, which accumulates in response to different types of cellular stress such as chemo‐ and radiotherapy, strongly induced expression of CD95‐L, cleavage of caspases and apoptosis. Antisense CD95‐L as well as dominant‐negative FADD inhibited ceramide‐ and cellular stress‐induced apoptosis. Fibroblasts from type A Niemann–Pick patients (NPA), genetically deficient in ceramide synthesis, failed to up‐regulate CD95‐L expression and to undergo apoptosis after γ‐irradiation or doxorubicin treatment. In contrast, JNK/SAPK activity was still inducible by doxorubicin in the NPA cells, suggesting that activation of JNK/SAPKs alone is not sufficient for induction of the CD95 system and apoptosis. CD95‐L expression and apoptosis in NPA fibroblasts were restorable by exogenously added ceramide. In addition, NPA fibroblasts undergo apoptosis after triggering of CD95 with an agonistic antibody. These data demonstrate that ceramide links cellular stress responses induced by γ‐irradiation or anticancer drugs to the CD95 pathway of apoptosis.

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

Different mechanisms may contribute to early T cell reconstitution in HIV-1-infected children and adolescents during ART: decreased activation-induced apoptosis leading to increased survival of circulating primed/memory T cells; decreased activation-induced naive-to-memory shift increasing the frequency of circulating resting/naive T cells; increased input of haematopoietic progenitor cells from the bone marrow into the thymus and decreased intrathymic T cell death leading to an increased thymic output of naive T cells.