A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators.

2.50
Hdl Handle:
http://hdl.handle.net/10541/87863
Title:
A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators.
Authors:
Wiemels, J L; Pagnamenta, A; Taylor, G M; Eden, Tim O B; Alexander, F E; Greaves, M F
Abstract:
Rearrangements and fusion of the MLL gene with various alternative partner genes occur in approximately 80% of infant leukemias and are acquired during fetal hemopoiesis in utero. Similar MLL gene recombinants also occur in topoisomerase II-inhibiting drug-induced leukemias. These data have led to the suggestion that some infant leukemia may arise via transplacental fetal exposures during pregnancy to substances that form cleavable complexes with topoisomerase II and induce illegitimate recombination of the MLL gene. A structural feature shared by many topoisomerase II-inhibiting drugs and other chemicals is the quinone moiety. We assayed, by PCR-RFLP, for a polymorphism in an enzyme that detoxifies quinones, NAD(P)H:quinone oxidoreductase (NQO1), in a series (n = 36) of infant leukemias with MLL rearrangements versus unselected cord blood controls (n = 100). MLL-rearranged leukemias were more likely to have genotypes with low NQO1 function (heterozygous CT or homozygous TT at nucleotide 609) than controls (odds ratio, 2.5; P = 0.015). In contrast, no significant allele bias was seen in other groups of pediatric leukemias with TEL-AML1 fusions (n = 50) or hyperdiploidy (n = 29). In the subset of infant leukemias that had MLL-AF4 fusion genes (n = 21), the bias increase in low or null function NQO1 genotypes was more pronounced (odds ratio, 8.12; P = 0.00013). These data support the idea of a novel causal mechanism in infant leukemia involving genotoxic exposure in utero and modulation of impact on a selective target gene by an inherited allele encoding a rate-limiting step in a carcinogen detoxification pathway.
Affiliation:
Leukaemia Research Fund Centre, Institute of Cancer Research, London, United Kingdom.
Citation:
A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. 1999, 59 (16):4095-9 Cancer Res.
Journal:
Cancer Research
Issue Date:
15-Aug-1999
URI:
http://hdl.handle.net/10541/87863
PubMed ID:
10463613
Type:
Article
Language:
en
ISSN:
0008-5472
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorWiemels, J Len
dc.contributor.authorPagnamenta, Aen
dc.contributor.authorTaylor, G Men
dc.contributor.authorEden, Tim O Ben
dc.contributor.authorAlexander, F Een
dc.contributor.authorGreaves, M Fen
dc.date.accessioned2009-12-14T14:43:30Z-
dc.date.available2009-12-14T14:43:30Z-
dc.date.issued1999-08-15-
dc.identifier.citationA lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. 1999, 59 (16):4095-9 Cancer Res.en
dc.identifier.issn0008-5472-
dc.identifier.pmid10463613-
dc.identifier.urihttp://hdl.handle.net/10541/87863-
dc.description.abstractRearrangements and fusion of the MLL gene with various alternative partner genes occur in approximately 80% of infant leukemias and are acquired during fetal hemopoiesis in utero. Similar MLL gene recombinants also occur in topoisomerase II-inhibiting drug-induced leukemias. These data have led to the suggestion that some infant leukemia may arise via transplacental fetal exposures during pregnancy to substances that form cleavable complexes with topoisomerase II and induce illegitimate recombination of the MLL gene. A structural feature shared by many topoisomerase II-inhibiting drugs and other chemicals is the quinone moiety. We assayed, by PCR-RFLP, for a polymorphism in an enzyme that detoxifies quinones, NAD(P)H:quinone oxidoreductase (NQO1), in a series (n = 36) of infant leukemias with MLL rearrangements versus unselected cord blood controls (n = 100). MLL-rearranged leukemias were more likely to have genotypes with low NQO1 function (heterozygous CT or homozygous TT at nucleotide 609) than controls (odds ratio, 2.5; P = 0.015). In contrast, no significant allele bias was seen in other groups of pediatric leukemias with TEL-AML1 fusions (n = 50) or hyperdiploidy (n = 29). In the subset of infant leukemias that had MLL-AF4 fusion genes (n = 21), the bias increase in low or null function NQO1 genotypes was more pronounced (odds ratio, 8.12; P = 0.00013). These data support the idea of a novel causal mechanism in infant leukemia involving genotoxic exposure in utero and modulation of impact on a selective target gene by an inherited allele encoding a rate-limiting step in a carcinogen detoxification pathway.en
dc.language.isoenen
dc.subjectLeukaemiaen
dc.subjectMyeloid-Lymphoid Leukaemia Proteinen
dc.subject.meshAcute Disease-
dc.subject.meshAdult-
dc.subject.meshAlleles-
dc.subject.meshChild-
dc.subject.meshChild, Preschool-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshFemale-
dc.subject.meshGene Rearrangement-
dc.subject.meshHumans-
dc.subject.meshInfant-
dc.subject.meshLeukemia-
dc.subject.meshLoss of Heterozygosity-
dc.subject.meshMyeloid-Lymphoid Leukemia Protein-
dc.subject.meshNAD(P)H Dehydrogenase (Quinone)-
dc.subject.meshPregnancy-
dc.subject.meshProto-Oncogenes-
dc.subject.meshTranscription Factors-
dc.titleA lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators.en
dc.typeArticleen
dc.contributor.departmentLeukaemia Research Fund Centre, Institute of Cancer Research, London, United Kingdom.en
dc.identifier.journalCancer Researchen

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