title: The Wilms' tumor suppressor WT1 enhances CD95L expression and promotes activation-induced cell death in leukemic T cells.
abstract: The role of Wilms' tumor suppressor 1 (WT1) in leukemogenesis has been investigated mostly in acute (AML) and chronic (CML) myeloid leukemias. So far, its oncogenic role has been controversially discussed because both overexpression and inactivating mutations are found. A recent study on primary samples from patients with acute T-cell leukemia (T-ALL) revealed that most of them do not express WT1 proteins although they express WT1 mRNA. In our study, we investigated WT-1 expression in ten T-ALL cell lines established from leukemia/lymphoma patients. We show that consistent with the finding in primary T-ALL cells, most of the leukemic T-cell lines tested do not overexpress WT1 proteins. We found that leukemic T-cells overexpressing WT1 protein produce higher levels of CD95L and show elevated CD95L-mediated activation-induced cell death (AICD) compared to cells lacking or expressing low levels of WT1. Ectopic expression of WT1 in the WT1-nonexpressing leukemic T-cell line increases CD95L expression and elevates activation-induced apoptosis, whereas silencing WT1 expression in the WT1-overexpressing leukemic T-cell line by siRNA confers reduced CD95L expression and reduction in AICD. Chromatin immunoprecipitation and luciferase-promoter reporter analysis demonstrate that WT1 binds to and enhances CD95L promoter activity through the Egr-binding sites. Our study provides a new role of WT1 in regulation of CD95L-mediated cell death.
authors.affiliation: Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Bourkoula
authors.forename: Christoph
authors.initials: C
authors.lastname: Englert
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025721:WT1 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025721:WT1 Proteins
keywords: CD95 ligand; WT1; apoptosis; leukemia; transcriptional regulation