CD95 (APO-1/Fas) mutations in childhood T-lineage acute lymphoblastic leukemia.
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.
Beltinger
C
C
Sektion Hämatologie/Onkologie, Universitäts-Kinderklinik, Heidelberg, Germany.
Kurz
E
E
Böhler
T
T
Schrappe
M
M
Ludwig
W D
WD
Debatin
K M
KM
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D017209:Apoptosis; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D016384:Consensus Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006579:Heterozygote; D006801:Humans; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012008:Recurrence; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics*
D000305:Adrenal Cortex Hormones; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D019014:fas Receptor