A lack of a functional NAD(P)H : quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions

Citation
Jl. Wiemels et al., A lack of a functional NAD(P)H : quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions, CANCER RES, 59(16), 1999, pp. 4095-4099
Citations number
59
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
59
Issue
16
Year of publication
1999
Pages
4095 - 4099
Database
ISI
SICI code
0008-5472(19990815)59:16<4095:ALOAFN>2.0.ZU;2-2
Abstract
Rearrangements and fusion of the MLL gene with various alternative partner genes occur in similar to 80% of infant leukemias and are acquired during f etal hemopoiesis in utero. Similar MLL gene recombinants also occur in topo isomerase II-inhibiting drug-induced leukemias, These data have led to the suggestion that some infant leukemia may arise via transplacental fetal exp osures during pregnancy to substances that form cleavable complexes with to poisomerase II and induce illegitimate recombination of the MLL gene. A str uctural feature shared by many topoisomerase II-inhibiting drugs and other chemicals is the quinone moiety, We assayed, by PCR-RFLP, for a polymorphis m in an enzyme that detoxifies quinones, NAD(P)H:quinone oxidoreductase (NQ O1), in a series (n = 36) of infant leukemias with MLL rearrangements versu s unselected cord blood controls (n = 100). MLL-rearranged leukemias were m ore likely to have genotypes with Low NQO1 function (heterozygous CT or hom ozygous TT at nucleotide 609) than controls (odds ratio, 2.5; P = 0.015). I n contrast, no significant allele bias was seen in other groups of pediatri c leukemias with TEL-AML1 fusions (n = 50) or hyperdiploidy (n = 29). In th e subset of infant Leukemias that had MLL-AF4 fusion genes (n = 21), the bi as increase in low or null function NQO1 genotypes was more pronounced (odd s 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 modu lation of impact on a selective target gene by an inherited allele encoding a rate-limiting step in a carcinogen detoxification pathway.