Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Infant ALL

Genetic polymorphism of NAD(P)H:quinone oxidoreductase is associated with an increased risk of infant acute lymphoblastic leukemia without MLL gene rearrangements

Leukemia volume 19, pages 214–216 (2005)Cite this article

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a detoxification enzyme that protects cells against oxidative stress and toxic quinones. A polymorphism (C609T) in the gene produces in the heterozygous individuals (C/T) a reduction and in those homozygous for the variant allele (T/T) the abolishment of NQO1 protein activity. To assess whether NQO1 inactivating polymorphism (CT/TT) was a possible risk factor for infant acute lymphoblastic leukemia (iALL), we investigated the distribution of NQO1 genotype in 50 iALL patients, 32 with MLL gene rearrangements (MLL+) and 18 without (MLL−). As controls, 106 cases of pediatric ALL (pALL), and 147 healthy subjects were also studied. Compared to normal controls, the frequency of the low/null activity NQO1 genotypes was significantly higher in the iALL MLL− (72 vs 38%, P=0.006; odds ratio (OR) 4.22, 95% confidence interval (CI) 1.43–12.49), while no differences were observed in iALL MLL+ (44 vs 38%, P=0.553; OR 1.26, 95% CI 0.58–2.74). Similar results were observed when pALL were used as control. Our results indicate that only the iALL patients without MLL rearrangements had a significantly higher frequency of NQO1 genotypes associated with low/null activity enzyme, suggesting a possible role for NQO1 gene as an MLL-independent risk factor, in the leukemogenic process of this subtype of iALL.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

References

  1. Pui CH, Kane JR, Crist WM . Biology and treatment of infant leukemia. Leukemia 1995; 9: 762–769.

    CAS  PubMed  Google Scholar 

  2. Greaves MF . Infant leukemia biology, aetiology and treatment. Leukemia 1996; 10: 372–377.

    CAS  PubMed  Google Scholar 

  3. Biondi A, Cimino G, Pieters R, Pui CH . Biological and therapeutic aspects of infant leukemia. Blood 2000; 96: 24–33.

    CAS  PubMed  Google Scholar 

  4. Hunger SP, McGavran L, Meltesen L, Parker NB, Kassenbrock CK, Bitter MA . Oncogenesis in utero: fetal death due to acute myelogenous leukemia with an MLL translocation. Br J Haematol 1998; 103: 539–542.

    Article  CAS  PubMed  Google Scholar 

  5. Ford AM, Ridge SA, Cabrera ME, Mahmoud H, Steel CM, Chan LC et al. In utero rearrangements in the trithorax-related oncogene in infants leukemias. Nature 1993; 363: 358–360.

    Article  CAS  PubMed  Google Scholar 

  6. Gill Super HJ, Rothberg PG, Kobayashi H, Freeman AI, Diaz MO, Rowley JD . Clonal, non constitutional rearrangements of the MLL gene in infant twins with the acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23. Blood 1994; 83: 641–644.

    CAS  PubMed  Google Scholar 

  7. Greaves MF, Maia AT, Wiemels JL, Ford AM . Leukemia in twins: lesson in natural history. Blood 2003; 102: 2321–2333.

    Article  CAS  PubMed  Google Scholar 

  8. Greaves M . Aetiology of acute leukemia. Lancet 1997; 349: 344–349.

    Article  CAS  PubMed  Google Scholar 

  9. Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PU, Ross D et al. NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomicina sensitivity. Cancer Res 1992; 52: 797–802.

    CAS  PubMed  Google Scholar 

  10. Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF, the United Kingdom Childhood Cancer Study Investigators. A lack of function NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. Cancer Res 1999; 59: 4095–4099.

    CAS  PubMed  Google Scholar 

  11. Smith MT, Wang Y, Skibola CF, Slater DJ, Lo Nigro L, Nowell PC et al. Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children. Blood 2002; 100: 4590–4593.

    Article  CAS  PubMed  Google Scholar 

  12. Eickelmann P, Schulz WA, Rohde D, Schmitz-Drager B, Sies H . Loss of heterozygosity at the NAD(P)H:quinone oxidoreductase locus associated with increased resistance against mitomicina C in a human bladder carcinoma cell line. Biol Chem Hoppe-Seyler 1994; 375: 439–445.

    Article  CAS  PubMed  Google Scholar 

  13. Gaedigk A, Tyndale RF, Jurima-Romet M, Sellers EM, Grant DM, Leeder JS . NAD(P)H:quinone oxidoreductase polymorphisms and allele frequencies in Caucasian, Chinese, and Canadian Native Indian and Inuit Populations. Pharmacogenetics 1998; 8: 305–313.

    Article  CAS  PubMed  Google Scholar 

  14. Ernester L . DT-diaphorase: its structure, function, regulation, and role in antioxidant defence and cancer chemotherapy. In: Yagi K (ed). Pathophysiology of Lipid Peroxides and Related Free Radicals. Basel, Switzerland: S Karger, 1998, pp 149–168.

    Google Scholar 

  15. Ross D . Quinone reductases. In: Guengerich FP (ed). Comprehensive Toxicology, Vol. 3. New York, NY: Pergamon Press, 1997, pp 179–197.

    Google Scholar 

  16. Asher G, Lotem J, Kama R, Sachs L, Shaul Y . NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci USA 2002; 99: 3099–3104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Anwar A, Dehn D, Siegel D, Kepa JK, Tang LJ, Pieterpol JA et al. Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems. J Biol Chem 2003; 278: 10368–10373.

    Article  CAS  PubMed  Google Scholar 

  18. Cimino G, Rapanotti M, Biondi A, Elia L, Lo Coco F, Price C et al. Infant acute leukemias show the same biased distribution of ALL1 gene breaks as topoisomerase II related secondary acute leukemias. Cancer Res 1997; 57: 2879–2883.

    CAS  PubMed  Google Scholar 

  19. Blanco JG, Edick MJ, Hancock ML, Winick NJ, Derveux T, Amylon MD et al. Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies. Pharmacogenetics 2002; 12: 605–611.

    Article  CAS  PubMed  Google Scholar 

  20. Garte S, Taioli E, Crosti F, Sainati L, Barisone E, Luciani M et al. Deletion of parental GST genes as a possible susceptibility factor in the etiology of infant leukemia. Leukemia Res 2000; 24: 971–974.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by project Ministero Sanità 01, X, 000177; Fondazione Città della Speranza; Progetto finalizzato MIUR-CNR; Compagnia di S Paolo; Fondazione CARIGE.

Author information

Authors and Affiliations

  1. Hematology Unit, Department of Pediatric Hemato-Oncology, G Gaslini Children's Hospital, Genova, Italy

    M Lanciotti, C Dufour, P Di Michele, S Pigullo & C Micalizzi

  2. Centro Ricerca Tettamanti, Pediatric Clinic, University of Milano Bicocca, Monza, Italy

    L Corral & A Biondi

  3. Hematology Division, Bambin Gesù Children's Hospital, Roma, Italy

    G De Rossi & M Luciani

  4. Pediatric Onco-Hematology Clinic University of Padova, Padova, Italy

    G Basso & A Leszl

  5. Center of Pediatric Hemato-Oncology, University of Catania, Catania, Italy

    L Lo Nigro

  6. Section of Medical Statistics, University of Milano-Bicocca, Monza, Italy

    M G Valsecchi

  7. Epidemiology and Biostatistics Section, Scientific Directorate G Gaslini Children's Hospital, Genova, Italy

    R Haupt

Authors
  1. M Lanciotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Dufour
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Corral
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Di Michele
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Pigullo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G De Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Basso
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Leszl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Luciani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L Lo Nigro
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C Micalizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M G Valsecchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A Biondi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R Haupt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Lanciotti.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lanciotti, M., Dufour, C., Corral, L. et al. Genetic polymorphism of NAD(P)H:quinone oxidoreductase is associated with an increased risk of infant acute lymphoblastic leukemia without MLL gene rearrangements. Leukemia 19, 214–216 (2005). https://doi.org/10.1038/sj.leu.2403613

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403613

Keywords

  • NQO1 polymorphism
  • infant leukemia
  • MLL gene rearrangement

This article is cited by

Search

Advanced search

Quick links