title: Loss of imprinting of IGF-II gene in children with acute lymphoblastic leukemia.
abstract: Insulin-like growth factor-II (IGF-II) is known to be involved in the regulation of growth, differentiation and cell death in normal human tissues. In a variety of human tumors, the IGF-II gene is overexpressed and considered to be a stimulator for tumor growth through autocrine and paracrine mechanisms. The IGF-II gene is normally parental imprinted, only the paternal allele being expressed in most tissues. Several reports about biallelic expression (loss of imprinting (LOI)) of the IGF-II gene in different tumors suggest a role of dysregulation of IGF-II imprinting in tumorigenesis. However, biallelic expression of IGF-II gene has also been reported in different tissues of a significant number of normal controls, indicating either a normal phenomenon or an elevated cancer risk in this group of persons. Although LOI of IGF-II presumably promotes tumorigenesis by increasing IGF-II expression, elevated IGF-II levels in those patients have not been reported. We studied IGF-II gene expression in malignant lymphoblasts of 124 children suffering from acute lymphoblastic leukemia, 196 cord blood samples from healthy newborns and mononuclear cells (MNC) from 50 healthy age matched children. The ApaI polymorphism in exon 9 of the IGF-II gene and allele-specific exon-connection RT-PCR was used for determination of the imprinting status. From 44 informative ALL-patients, 24 (54%) showed LOI of the IGF-II gene. Twenty percent of the informative cord blood samples (N=56) and 14% of the informative MNC samples from healthy controls (N=22) showed biallelic expression of IGF-II. In the ALL-patients, no statistical significant correlation between LOI patients and relapse rate, surviving rate and risk groups could be detected. We conclude that LOI of IGF-II occurs in malignant lymphoblasts of children suffering from acute lymphoblastic leukemia in more than 50% of the patients. In MNC from cord blood and peripheral MNC from healthy controls, biallelic expression could be detected in up to 20% of all cases. The importance of LOI in ALL-patients needs to be further evaluated to determine its impact in leukemogenesis.
authors.affiliation: Department of Pediatric Oncology, Otto von Guericke University, Emanuel-Larisch-Weg 17-19, D-39112 Magdeburg, Germany. peter.vorwerk@medizin.uni-magdeburg.de
authors.forename: Peter
authors.initials: P
authors.lastname: Vorwerk
authors.forename: Heike
authors.initials: H
authors.lastname: Wex
authors.forename: Cornelia
authors.initials: C
authors.lastname: Bessert
authors.forename: Bianka
authors.initials: B
authors.lastname: Hohmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Schmidt
authors.forename: Uwe
authors.initials: U
authors.lastname: Mittler
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D017931:DNA Primers / Q000737:chemistry; D015252:Deoxyribonucleases, Type II Site-Specific; D005260:Female; D005312:Fetal Blood / Q000737:chemistry / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
chemical_list: D017931:DNA Primers; D007335:Insulin-Like Growth Factor II; D015252:Deoxyribonucleases, Type II Site-Specific; C038485:GGGCCC-specific type II deoxyribonucleases