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[Cancer Research 59, 4095-4099, August 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 4095-4099, August 15, 1999]
© 1999 American Association for Cancer Research

Molecular Biology and Genetics

A Lack of a Functional NAD(P)H:Quinone Oxidoreductase Allele Is Selectively Associated with Pediatric Leukemias That Have MLL Fusions1

Joseph L. Wiemels, Alistair Pagnamenta, G. Malcolm Taylor, Osborn B. Eden, Freda E. Alexander, Mel F. Greaves2 and United Kingdom Childhood Cancer Study Investigators,3

Leukaemia Research Fund Centre, Institute of Cancer Research, London SW3 6JB [J. L. W., A. P., M. F. G.]; Immunogenetics Laboratory, St Mary’s Hospital, Manchester M13 0JH [G. M. T.]; Academic Unit of Paediatric Oncology, Royal Manchester Children’s and Christie Hospital National Health Service Trust, Withington, Manchester M20 4BX [O. B. E.]; and Department of Public Health Sciences, University of Edinburgh, Medical School, Edinburgh EH8 9AG [F. E. A.], United Kingdom

Rearrangements and fusion of the MLL gene with various alternative partner genes occur in ~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.




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