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
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.