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CD95 (APO-1/Fas) mutations in childhood T-lineage acute lymphoblastic leukemia

Item Type:Article
Title:CD95 (APO-1/Fas) mutations in childhood T-lineage acute lymphoblastic leukemia
Creators Name:Beltinger, C. and Kurz, E. and Boehler, T. and Schrappe, M. and Ludwig, W.D. and Debatin, K.M.
Abstract:CD95 (APO-1/Fas)-mediated apoptosis is pivotal in normal lymphocyte homeostasis and mutations of CD95 cause a benign autoimmune lymphoproliferation syndrome (ALPS) in humans and mice. However, tumors only rarely develop in these patients, and no CD95 mutations have yet been directly implicated in tumorigenesis. We therefore examined 81 de novo childhood T-lineage acute lymphoblastic leukemias (T-ALL) including 54 steroid-poor responders, 10 relapsed T-ALL, and 10 leukemic T-cell lines, for the presence of CD95 mutations using single-strand confirmation polymorphism and sequence analysis. In leukemic blasts and normal T cells of one patient, a heterozygous mutation in exon 3 of CD95 causing a 68Pro --> 68Leu change associated with decreased CD95-mediated apoptosis was found. In leukemic blasts and normal T cells of a second patient, a homozygous mutation in the promoter of CD95 causing disruption of a consensus sequence for AP-2 binding without decreasing constitutive CD95 expression was detected. No large intragenic alterations of CD95 were found, no homozygous loss was detected in the cell lines, and no CD95 mutations were detected in the relapses. The data presented here show that CD95 mutations occur in some T-ALL and may be of biological importance.
Keywords:Adrenal Cortex Hormones, CD95 Antigens, Apoptosis, Binding Sites, Consensus Sequence, DNA Mutational Analysis, Neoplasm DNA, DNA-Binding Proteins, Neoplasm Drug Resistance, Exons, Fatal Outcome, Leukemic Gene Expression Regulation, Heterozygote, Adult T-Cell Leukemia-Lymphoma, Neoplasm Proteins, Polymerase Chain Reaction, Restriction Fragment Length Polymorphism, Single-Stranded Conformational Polymorphism, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Genetic Promoter Regions, Recurrence, Transcription Factor AP-2, Cultured Tumor Cells
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Volume:91
Number:10
Page Range:3943-3951
Date:15 May 1998
Official Publication:http://bloodjournal.hematologylibrary.org/cgi/content/abstract/91/10/3943
PubMed:View item in PubMed

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