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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
By
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.
 |
ABSTRACT |
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.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THE WIDESPREAD USE of intensive
combination chemotherapy regimens and megavoltage radiation therapy has
resulted in steadily improving long-term survival among patients in
whom cancer had previously been fatal. This therapeutic success has led
to the survival of large numbers of patients who formerly were destined to die within a few years. One of the most serious consequences of
cancer therapy is the development of a second cancer, especially myeloid leukemia. Therapy-related acute myeloid leukemia (t-AML) is a
neoplastic hematopoietic disorder arising in most cases from a
multipotent stem cell and, in a few cases, from a lineage-committed progenitor.1 The term therapy-related leukemia is
descriptive and is based on a patient's history of exposure to
cytotoxic agents. Although a causal relationship is implied, the
mechanism of this remains to be proven. This term may ultimately be too
restrictive, because the leukemias that develop after exposure to
benzene or to atomic bomb irradiation are very similar or identical to
the therapy-related leukemia syndrome.2
It has been known for many years that benzene causes hematotoxicity and
is also associated with AML.2-7 Many clinical reports suggest that individuals vary greatly in their susceptibility to
adverse health outcomes from benzene exposure. One explanation for this
diversity is interindividual variation in metabolic activation and
detoxification of benzene in humans.8,9
Benzene is metabolized by the hepatic enzyme cytochrome P4502E1
(CYP2E1) to benzene oxide, which spontaneously forms phenol and is
itself further metabolized by CYP2E1 to hydroquinone.9 Hydroquinone and related hydroxy metabolites are converted in the bone
marrow by myeloperoxidase to benzoquinones.10,11 These latter compounds are potent hematotoxins and genotoxins that can be
converted by the enzyme NAD(P)H:quinone oxidoreductase (NQO1) to less
toxic hydroxy metabolites. It has recently been shown in a case-control
study of benzene-poisoned workers in Shanghai, China that lack of NQO1
enzyme activity was associated with benzene poisoning, leading to
hematotoxicity.9
NQO1 encodes an enzyme also known as DT-diaphorase. This enzyme is a
dimeric flavin adenine dinucleotide (FAD)-containing cytosolic protein
that catalyzes the 2 electron reduction of a variety of quinone
compounds.12 The reduction of the quinone moiety to a
hydroquinone prevents the generation of free radicals and reactive
oxygen species, thus protecting cells from oxidative damage. However,
the NQO1 enzyme also functions as a mechanism for the reduction and
ultimate activation of certain chemotherapeutic drugs and of
environmental carcinogens such as nitroaromatic compounds, heterocyclic
amines, and possibly cigarette smoke condensate.13-17
The NQO1 gene locus maps to chromosome band 16q23. A polymorphism
exists due to a C T substitution at nucleotide 609 in the cDNA, giving rise to a missense mutation in codon 187 (proline-serine).16-19 Among Northern Europeans and
Caucasian Americans, the gene frequency is 0.79 for the wild-type
allele and 0.21 for the mutated allele.17,20-22 The
frequency of the mutated allele is known to be slightly higher among
African Americans and considerably higher among Hispanics and
Asians.9,17,22 NQO1 enzyme activity is normal in
individuals with 2 wild-type alleles. It is variably reduced in
individuals who are heterozygotes for the polymorphism.19
The NQO1 protein and activity are absent in those who are homozygous
for the point mutation.20
We have been interested in trying to understand whether the development
of therapy-related leukemia is a stochastic process (occurring by
chance) or whether it is idiosyncratic, ie, whether certain individuals
are at greater risk.1,23-25 The majority of t-AML cases are
associated with alkylating agents or radiotherapy and are characterized
by a median latency of 5 to 7 years, trilineage hematopoietic
dysplasia, and the loss or deletion of chromosomes 5 and/or
7.1,26 Similar features are thought to characterize benzene-associated AML.5,27 A smaller proportion of cases is associated with exposure to topoisomerase-II-inhibiting drugs, suggesting a different mechanism of leukemogenesis.1,28,29 These cases are characterized by a shorter latency, a monocytic phenotype, and balanced translocations involving the MLL gene at chromosome band 11q23 or the AML1 gene at band 21q22.
Our hypothesis is that the frequency of the 609CT
base substitution that results in an inactivating polymorphism in the
NQO1 gene differs between different subgroups of patients with AML and
will be greatest in those patients who develop t-AML after chemotherapy
and in those with abnormalities of chromosomes 5 or 7.
| |
MATERIALS AND METHODS |
Patients with various myeloid leukemias gave informed consent for
collection of blood and bone marrow specimens for this research. To
perform this study, karyotypes were prepared by cytogenetic analysis on
pretreatment bone marrow cells from leukemia patients using previously
described methods.30 Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines were established from peripheral blood B
lymphocytes from the same leukemia patients and provided the DNA from
nonmalignant cells.31 Polymerase chain reaction (PCR) primers were used to amplify DNA from exon 6 of the NQO1 gene. Restriction enzyme digestion with Hinf1 gave 3 possible
patterns of bands: a 271-bp band in those patients who were wild-type
homozygotes; 3 bands of 271, 151, and 120 bp in heterozygotes; and 2 bands of 151 and 120 bp in patients who were homozygous for the mutation.
DNA was isolated using conventional methods. The DNA was PCR-amplified
by the method developed by Eickelmann et al,32 with the
following modifications. The sense primer NQO1 F (5'-AAG CCC AGA
CCA ACT TCT-3') and antisense primer DT-2 (5'-TCT CCT CAT CCT GTA CCT CT-3') amplified a 304-bp region, including the NQO1 polymorphism, using a hot start protocol. DNA (1.5 µL; 0.1 to 0.5 µg), 25 pmol of each primer, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH
8.3), 2.5 pmol of each dNTP, 5% dimethyl sulfoxide (DMSO), and 2.5 U
Taq polymerase in a total volume of 50 µL were subjected to 40 cycles
(94°C for 50 seconds, 52°C for 50 seconds, and 72°C for 30 seconds) followed by an extension at 72°C for 10 minutes. The PCR
products were electrophoresed in 2% agarose.
A nested PCR method was used if regular PCR failed. The DNA was first
PCR amplified with the sense primer NQO1 454A (5'-GAG ACG CTA GCT
CTG AAC TGA T-3') and antisense primer NQO1 454B (5'-GGA AAT CCA GGC TAA GGA AT-3'). DNA (0.1 µL; 10 ng/µL), 25 pmol
of each primer, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3), 2.5 pmol of
each dNTP, and 2.5 U Taq polymerase in a total volume of 50 µL were
subjected to 35 cycles (94°C for 30 seconds and 58°C for 30 seconds). A second nested PCR using 1 µL of the first PCR product was
performed with the same reagents and primers NQO1 F and DT-2 as
described above.
PCR products were ethanol precipitated and digested with 10 U
Hinf1 enzyme at 37°C for 2 hours or overnight. The
digestion was stopped by heating to 65°C for 5 minutes.
The polymorphism was detected on an 8% polyacrylamide gel. Undigested
DNA was 304 bp. One Hinf I restriction site cuts a 33-bp fragment in all samples, acting as a digestion control. The restriction site polymorphism is a second HinfI site and results in three different combinations of bands: only one band of 271 bp corresponding to the genotype of homozygotes for the wild-type allele (C/C); three
bands with 271, 151, and 120 bp in length corresponding to the genotype
of heterozygotes (C/T); and two bands with 151 and 120 bp in length,
corresponding to the genotype of homozygotes for the mutant allele
(T/T).
Statistical considerations.
It should be kept in mind that this is a selected series of patients.
That is, the 104 patients who were studied all had myeloid leukemia,
were referred for evaluation to the University of Chicago, provided a
sample of blood or bone marrow, were successfully karyotyped, and had
an EBV-transformed lymphoblastoid cell line successfully generated.
Cell lines were selected for analysis for the NQO1 polymorphism based
on the knowledge of the clinical diagnosis and the karyotype.
Prospective unselected studies will be needed to validate the
observations described herein.
The following allele frequencies for the NQO1 polymorphism within
different ethnic groups were used: Caucasian, 0.21; African American,
0.23; Hispanic, 0.39; and Asian, 0.45.9,17,20-22 The expected values for the control group that we used for calculating statistical significance were taken from the literature involving different (although ethnically similar) populations. Conclusions based
on prevalence estimates drawn from such external populations are less
reliable. The  2 distribution was used to test for
statistical significance between the observed frequencies of the NQO1
polymorphism and the frequencies expected in a population with the same
ethnic mix.
| |
RESULTS |
We studied 104 patients with myeloid leukemias. Their characteristics
are shown in Table 1. Fifty-six had
developed t-AML after treatment with cytotoxic drugs or radiotherapy.
The other 48 patients had primary myelodysplastic syndrome (MDS; 30 patients), AML de novo (9 patients), or chronic myelogenous leukemia
(CML; 9 patients).
The frequencies with which the NQO1 polymorphism was detected in 48 patients with primary MDS, AML de novo, or CML are compared with that
for the 56 patients with t-AML in Table 2.
Also shown are the expected frequencies of NQO1 polymorphism for a
population with the same racial and ethnic composition as these 104 patients. Thus, we would expect that approximately 61% of our entire
cohort would have 2 wild-type alleles, 34% would be heterozygotes, and 5% would be homozygous for the mutation. We found that the frequency of homozygous mutants was 4% among the primary leukemia patients and
11% among those with t-AML. Heterozygotes were also more common among
both types of leukemia patients than expected in the general population. The frequency of the NQO1 polymorphism was significantly increased among all 104 patients (P = .050) and among the 56 patients with t-AML (P = .036) compared with the frequency
expected. The allele frequency for the polymorphism observed among the
t-AML patients was increased approximately 1.4-fold over that expected.
The median age at the time of first exposure to cytotoxic therapy for
the 27 t-AML patients with wild-type alleles was 48 years (range, 11 to
73 years). The median age for the 23 t-AML patients with heterozygosity
was 51 years (range, 7 to 82 years) and for the 6 t-AML patients who
were homozygous for the NQO1 polymorphism was 52 years (range, 32 to 69 years).
In Table 3 are shown the specific
cytogenetic rearrangements detected in the leukemia cells from these
patients and the observed frequency of NQO1 polymorphism within each
subgroup. Of the 13 patients with an abnormality of chromosome 5, 23%
were homozygous for the mutation. Of the 16 with an abnormality of
chromosome 7, 19% were homozygous, 56% were heterozygous, and only
25% had 2 wild-type alleles. An additional 16 patients had
abnormalities of both chromosomes 5 and 7, and 1 (6%) of these was
homozygous and 6 (38%) were heterozygous. There were no homozygous
mutants among the 33 patients with a balanced translocation involving bands 11q23, or 21q22, or an inv(16), t(15;17), or t(9;22). Fourteen patients had other clonal abnormalities, and 15 patients had a normal
karyotype.
In Table 4, the 45 patients with clonal
abnormalities of chromosomes 5 or 7 or both are examined more closely.
Thirty-six (80%) were Caucasian, 8 (18%) African American, and 1 (2%) was Hispanic. Forty-seven percent were observed to have 2 wild-type alleles, whereas 61% were expected. Thirty-eight percent
were heterozygotes, whereas 34% were expected. Sixteen percent had 2 mutant alleles and, therefore, likely had no enzyme activity; only 5%
were expected (P = .002). The mutant allele frequency was
calculated to be 0.34 among these 45 patients, and this was increased
approximately 1.6-fold over what was expected. In contrast, among the
33 leukemia patients with balanced translocations, the mutant allele
frequency was 0.23, or approximately what would be expected in the
general population.
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Table 4.
Frequency of the NQO1 Polymorphism in 45 Primary and
Therapy-Related Myeloid Leukemia Patients With Clonal Abnormalities of
Chromosomes 5 and/or 7
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We also analyzed our data to see if the frequency of NQO1 polymorphism
correlated with the primary treatment that had been received by these
56 t-AML patients. This was made difficult by the fact that most of our
patients had received multiple chemotherapy agents in various
combinations or together with radiation therapy. We grouped patients
according to their exposures to alkylating agents, topoisomerase II
inhibitors, antimetabolites, antitubulin drugs (principally vinca
alkaloids), and radiotherapy (Table 5). In
most categories, the frequency of the NQO1 polymorphism was higher than
expected but not markedly so. For example, among the 43 patients who
had received an alkylating agent, the frequencies of both heterozygous
and homozygous mutations were increased over the number expected.
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Table 5.
The Frequency of the NQO1 Polymorphism in 56 t-AML
Patients According to Their Primary Cytotoxic Treatment
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| |
DISCUSSION |
Our hypothesis postulated that heterozygosity and homozygosity for the
base pair substitution in codon 187 of NQO1 were associated with a
functional decrease in the amount of quinone reductase activity and
that these individuals would have a markedly increased susceptibility
to the genotoxic and leukemogenic effects of cytotoxic therapy. This
hypothesis is supported by epidemiological data that have associated
the 609CT mutation of NQO1 with benzene-induced
hematotoxicity.9 Occupational benzene poisoning is itself
strongly associated with the subsequent development of AML and the
related MDS.2-7 Because benzene-associated leukemia has
clinical, morphologic, and cytogenetic features similar to the myeloid
leukemias that follow exposure to alkylating agents, we focused on the
frequency of NQO1 polymorphism in our patients who had AML with
abnormalities of chromosomes 5 and/or 7 and compared them with other
patients with myeloid leukemias characterized by balanced
translocations or normal karyotypes. It is reasonable to assume that
the mechanism of leukemogenesis between these two categories (ie, loss
or deletion of no. 5 or 7 and balanced translocations) is considerably
different.1,28,29
Although typically thought of as a detoxification mechanism, NQO1
activity is also a well-documented component of pathways for mutagen
and carcinogen activation.12-14 NQO1 is an inducible enzyme
and is increased, for example, by cigarette smoking. Lung cancer in
Mexican Americans and African Americans has been associated with the
wild-type genotype of the NQO1 polymorphism.16,17 In this
situation, functional NQO1 probably results in the activation of
potential lung carcinogens.
In summary, the frequency of an inactivating polymorphism in NQO1
appears to be increased in a cohort of myeloid leukemia patients with
abnormalities of chromosomes 5 and/or 7, but not in those with balanced
translocations, other clonal abnormalities, or normal karyotypes. Most
of the former group of patients had therapy-related AML. The mutant
allele frequency was approximately 1.6-fold higher than expected among
patients with abnormalities in chromosomes 5 and/or 7 and 1.4-fold
higher than expected among all patients with t-AML. Thus, individuals
who are homozygous for the inactivating allele of NQO1 and thereby
completely lack enzyme activity may be particularly vulnerable to
leukemogenic changes induced by carcinogens. Heterozygotes may share
this increased leukemogenic risk through two mechanisms. NQO1 enzyme
activity may be variably reduced in heterozygotes and then further
depleted by the oxidative stress of cytotoxic drugs, or these
individuals may experience a treatment-induced mutation or loss of the
remaining wild-type allele in one of their hematopoietic stem cells.
Further studies on a large population of patients are required to
confirm these findings.
| |
ACKNOWLEDGMENT |
The authors thank the many physicians who referred patients to the
University of Chicago for this study, Dr Theodore Karrison for his
statistical assistance, Dr Janet D. Rowley for her careful review of
the manuscript, and Melissa Ellifson and Marjorie Isaacson for their
expert data management.
| |
FOOTNOTES |
Submitted August 24, 1998; accepted March 19, 1999.
Supported in part by Grants No. PO1 CA40046 and CA14599 from the
National Cancer Institute (Bethesda, MD; to R.A.L. and M.M.L.B.) and by
the National Foundation for Cancer Research (to M.T.S.). J.W. was a
Howard Hughes Predoctoral Fellow.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Richard A. Larson, MD, University of
Chicago, MC-2115, 5841 S Maryland Ave, Chicago, IL 60637; e-mail:
ralarson{at}mcis.bsd.uchicago.edu.
| |
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Disruption of Dihydronicotinamide Riboside:Quinone Oxidoreductase 2 (NQO2) Leads to Myeloid Hyperplasia of Bone Marrow and Decreased Sensitivity to Menadione Toxicity
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TOP
ABSTRACT
INTRODUCTION