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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 803-807
Prevalence of the Inactivating 609C T Polymorphism
in the NAD(P)H:Quinone Oxidoreductase (NQO1) Gene in Patients With
Primary and Therapy-Related Myeloid Leukemia
Richard A. Larson,
Yunxia Wang,
Mekhala Banerjee,
Joseph Wiemels,
Christine Hartford,
Michelle M. Le Beau, and
Martyn T. Smith
From the Section of Hematology/Oncology, Department of Medicine and
the Cancer Research Center of the University of Chicago, Chicago, IL;
and the Division of Environmental Health Sciences, School of Public
Health, University of California, Berkeley, CA.
NAD(P)H:quinone oxidoreductase (NQO1) converts benzene-derived
quinones to less toxic hydroquinones and has been implicated in
benzene-associated hematotoxicity. A point mutation in codon 187 (Pro
to Ser) results in complete loss of enzyme activity in homozygous
subjects, whereas those with 2 wild-type alleles have normal activity.
The frequency of homozygosity for the mutant allele among Caucasians
and African Americans is 4% to 5% but is higher in Hispanics and
Asians. Using an unambiguous polymerase chain reaction (PCR) method, we
assayed nonmalignant lymphoblastoid cell lines derived from 104 patients with myeloid leukemias; 56 had therapy-related acute myeloid
leukemia (t-AML), 30 had a primary myelodysplastic syndrome (MDS), 9 had AML de novo, and 9 had chronic myelogenous leukemia (CML). All
patients had their leukemia cells karyotyped. Eleven percent of the
t-AML patients were homozygous and 41% were heterozygous for the NQO1
polymorphism; these proportions were significantly higher than those
expected in a population of the same ethnic mix (P = .036).
Of the 45 leukemia patients who had clonal abnormalities of chromosomes
5 and/or 7, 7 (16%) were homozygous for the inactivating polymorphism,
17 (38%) were heterozygous, and 21 (47%) had 2 wild-type alleles for
NQO1. Thus, NQO1 mutations were significantly increased compared with
the expected proportions: 5%, 34%, and 61%, respectively (P
= .002). An abnormal chromosome no. 5 or 7 was observed in 7 of 8 (88%) homozygotes, 17 of 45 (38%) heterozygotes, and 21 of 51 (41%) patients with 2 wild-type alleles. Among 33 patients with balanced translocations [14 involving bands 11q23 or 21q22, 10 with inv(16) or
t(15;17), and 9 with t(9;22)], there were no homozygotes, 15 (45%)
heterozygotes, and 18 (55%) with 2 wild-type alleles. Whereas fewer
than 3 homozygotes were expected among the 56 t-AML patients, 6 were
observed; 19 heterozygotes were expected, but 23 were observed. The
gene frequency for the inactivating polymorphism (0.31) was increased
approximately 1.4-fold among the 56 t-AML patients. This increase was
observed within each of the following overlapping cohorts of t-AML
patients: the 43 who had received an alkylating agent, the 27 who had
received a topoisomerase II inhibitor, and the 37 who had received any
radiotherapy. Thus, the frequency of an inactivating polymorphism in
NQO1 appears to be increased in this cohort of myeloid leukemias,
especially among those with t-AML or an abnormality of chromosomes 5 and/or 7. Homozygotes and heterozygotes (who are at risk for
treatment-induced mutation or loss of the remaining wild-type allele in
their hematopoietic stem cells) may be particularly vulnerable to
leukemogenic changes induced by carcinogens.
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