Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1)is an enzyme that detoxifies quinones and reduces oxidative stress. A cysteineto-threonine (C 3 T) substitution polymorphism at nucleotide 609 of the NQO1 complementary DNA (NQO1 C609T ) results in a lowering of NQO1 activity. Individuals homozygous for this mutation have no NQO1 activity, and heterozygotes have low to intermediate activity compared with people with wild type. DNA samples from 493 adult de novo acute leukemia patients and 838 matched controls were genotyped for NQO1 C609T. The majority of cases were diagnosed as acute myeloid leukemia (AML) (n ‫؍‬ 420); 67 as acute lymphoblastic leukemia (ALL); and 6 as other forms of acute leukemia. The frequency of cases with low or null NQO1 activity (heterozygote ؉ homozygous mutant) was significantly higher among total acute leukemia case subjects compared with their matched controls (odds ratio [ IntroductionClues to the etiology of leukemia may be gained through the study of genetic susceptibility in candidate genes. NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2), originally called DTdiaphorase, 1 is an enzyme that is able to detoxify a number of natural and synthetic compounds, including quinones and their derivatives. 2,3 It is induced by synthetic antioxidants and cruciferous vegetables 4,5 and protects cells against oxidative stress.A single nucleotide polymorphism (cysteine-to-threonine, [C 3 T]) at position 609 in the NQO1 gene has been identified in a human colon cancer cell line with very low NQO1 activity. 6 This variant produces a proline-to-serine substitution that inactivates the enzyme. People who are homozygous for the variant allele completely lack NQO1 activity, and heterozygotes have low to intermediate activity compared with people with the wild type. 7 The incidence of the polymorphism varies widely by race, 8 and associations have been made between the presence of variant alleles and lung and urological cancers. [9][10][11] Evidence that the NQO1 variant allele may be significantly overrepresented in therapy-related myeloid leukemias and in those with specific chromosome aberrations has been recently presented. 12 In addition, it has been reported that infant leukemias with MLL gene rearrangements have a significantly increased frequency of the NQO1 C609T allele. 13 The NQO1 C609T polymorphism has also been shown to be associated with a greater risk of leukopenia (low white blood cell counts) in benzene-exposed individuals. 14 Lack of, or low, NQO1 activity may therefore predispose individuals exposed to chemotherapy drugs and benzene to a greater risk of leukemia. These studies led us to ask whether low NQO1 activity may play a role in the etiology of adult acute leukemia in the general population. In the present study, we have applied a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay to survey the distribution of mutant NQO1 alleles in white patients with de novo acute leukemia and more than 800 control subjects. Patients and methods Case-control study p...

Polymorphism in glutathione S -transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

“…For this study, t-AML is defined as AML following chemotherapy and͞or radiotherapy diagnosed at least 2 months after the start of the initial cytotoxic therapy. All samples from the de novo AML and control groups, and 24 of those with t-AML, were routinely obtained as part of a large, population-based, case-control study of acute leukemia that has been fully described elsewhere (31,(41)(42)(43)(44). Briefly, all subjects were between 16 and 69 years of age and were diagnosed with AML between April 1991 and December 1996 while resident in parts of the north and southwest of England.…”

Effects of NQO1 deficiency on levels of cyclopurines and other oxidative DNA lesions in liver and kidney of young mice

“…49 Low NQO1 activity correlates with increased risk of acute leukemia in children 50 and adults. 51 Inactivating NQO1 FIGURE 4 -Linear correlations between NQO1 activity and levels of type II I-compounds in wild-type mice at 1-30 days of age. There were statistically significant negative linear correlations between NQO1 activity and total hepatic type II I-compound levels (a), combined hepatic spots 2 and 5 (b) and combined renal spots 2 and 5 (c).…”

CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor-risk karyotype associated with NRAS mutation, but not associated withFLT3 internal tandem duplication

“…This patient cohort overlaps with cohorts in previously published studies. 6 Median age was 46 years (range, 15-79 years). DNA was extracted from presentation bone marrow by dodecyltrimethylammonium bromide lysis 9 and stored at University College London (United Kingdom).…”

“…[6][7][8] Furthermore, this predisposition may be greater or less in subgroups of AML defined by specific genomic damage at the karyotypic level. The paradigm for an AML-predisposition gene encoding a carcinogen-metabolizing enzyme is NADP(H) quinone oxidoreductase (NQO1).…”

“…The C609T polymorphic variant, which confers reduced phase 2 metabolism, is associated with a predisposition to therapy-related AML 4 and selected cytogenetic subgroups of de novo AML. 6 Reduced phase 2 metabolism has the potential to result in an accumulation of reactive intermediates, which in turn oxidize DNA and protein, leading to DNA mutation and/or cell death. Phase 1 enzymes with functionally relevant allelic variants are also predisposition genes for AML and include cytochrome P450 2C19 (CYP2C19) and CYP2D6.…”