title: KIR ligand C2 is associated with increased susceptibility to childhood ALL and confers an elevated risk for late relapse.
abstract: A role for HLA class I polymorphism in childhood acute lymphoblastic leukemia (ALL) has been suggested for many years, but unambiguous associations have not been found. Here, we show that the HLA-C-encoded supertypic epitope C2, which constitutes a high-affinity ligand for the inhibitory natural killer (NK) cell receptor KIR2DL1, is significantly increased in ALL patients (n = 320; P = .005). Stratification for ethnicity and disease subtype revealed a strong association of C2 with B-ALL in German cases (P = .0004). The effect was independent of KIR2DS1 and KIR2DL1 allelic polymorphism and copy number. Analysis of clinical outcome revealed a higher incidence of late relapse (> 2.5 years) with increasing number of C2 alleles (P = .014). Our data establish C2 as novel risk factor and homozygosity for C1 as protective for childhood B-ALL supporting a model in which NK cells are involved in immunosurveillance of pediatric B-ALL via interaction of KIR with HLA-C ligands.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Düsseldorf, Germany;
authors.forename: Florian
authors.initials: F
authors.lastname: Babor
authors.affiliation: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University, Düsseldorf, Germany; and.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Manser
authors.affiliation: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University, Düsseldorf, Germany; and.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Fischer
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Düsseldorf, Germany;
authors.forename: Nadine
authors.initials: N
authors.lastname: Scherenschlich
authors.affiliation: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University, Düsseldorf, Germany; and.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Enczmann
authors.affiliation: Department of Pathology and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Olympe
authors.initials: O
authors.lastname: Chazara
authors.affiliation: Department of Pathology and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ashley
authors.initials: A
authors.lastname: Moffett
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Düsseldorf, Germany;
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Düsseldorf, Germany;
authors.forename: Roland
authors.initials: R
authors.lastname: Meisel
authors.affiliation: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University, Düsseldorf, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Uhrberg
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D000939:Epitopes / Q000737:chemistry; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D015236:HLA-C Antigens / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000166:cytology; D008024:Ligands; D008297:Male; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics*; D054342:Receptors, KIR2DL1 / Q000378:metabolism*; D012008:Recurrence; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000939:Epitopes; D015236:HLA-C Antigens; C093100:KIR2DL1 protein, human; D008024:Ligands; D054342:Receptors, KIR2DL1