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.

  • Original Article
  • Published:

Acute Leukemias

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

Leukemia volume 26, pages 1247–1254 (2012)Cite this article

Subjects

Abstract

Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French–American–British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P=0.02) and overall survival (5-year OS: 23% vs 45%, P=0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia 2008; 22: 915–931.

    Article  CAS  PubMed  Google Scholar 

  2. Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood 2003; 102: 1613–1618.

    Article  CAS  PubMed  Google Scholar 

  3. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 2003; 101: 837–845.

    Article  PubMed  Google Scholar 

  4. Barragan E, Cervera J, Bolufer P, Ballester S, Martin G, Fernandez P et al. Prognostic implications of Wilms’ tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica 2004; 89: 926–933.

    CAS  PubMed  Google Scholar 

  5. Heuser M, Argiropoulos B, Kuchenbauer F, Yung E, Piper J, Fung S et al. MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood 2007; 110: 1639–1647.

    Article  CAS  PubMed  Google Scholar 

  6. Lapillonne H, Renneville A, Auvrignon A, Flamant C, Blaise A, Perot C et al. High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol 2006; 24: 1507–1515.

    Article  CAS  PubMed  Google Scholar 

  7. Marcucci G, Haferlach T, Dohner H . Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011; 29: 475–486.

    Article  CAS  PubMed  Google Scholar 

  8. Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C et al. High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 2007; 25: 3337–3343.

    Article  CAS  PubMed  Google Scholar 

  9. Bullinger L, Kronke J, Schon C, Radtke I, Urlbauer K, Botzenhardt U et al. Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis. Leukemia 2010; 24: 438–449.

    Article  CAS  PubMed  Google Scholar 

  10. Raghavan M, Lillington DM, Skoulakis S, Debernardi S, Chaplin T, Foot NJ et al. Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res 2005; 65: 375–378.

    CAS  PubMed  Google Scholar 

  11. Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2009; 115: 453–474.

    Article  PubMed  Google Scholar 

  12. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    Article  CAS  PubMed  Google Scholar 

  13. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005; 106: 3740–3746.

    Article  PubMed  Google Scholar 

  14. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005; 106: 3733–3739.

    Article  CAS  PubMed  Google Scholar 

  15. Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 2005; 106: 3747–3754.

    Article  CAS  PubMed  Google Scholar 

  16. Renneville A, Boissel N, Gachard N, Naguib D, Bastard C, de Botton S et al. The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication. Blood 2009; 113: 5090–5093.

    Article  CAS  PubMed  Google Scholar 

  17. Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol 2010; 28: 570–577.

    Article  CAS  PubMed  Google Scholar 

  18. Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE . Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol 2010; 28: 2739–2747.

    Article  CAS  PubMed  Google Scholar 

  19. Pabst T, Eyholzer M, Fos J, Mueller BU . Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer 2009; 100: 1343–1346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011; 117: 2469–2475.

    Article  CAS  PubMed  Google Scholar 

  21. Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R . Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009; 113: 3088–3091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17: 225–234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–2433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yan XJ, Xu J, Gu ZH, Pan CM, Lu G, Shen Y et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 2011; 43: 309–315.

    Article  CAS  PubMed  Google Scholar 

  26. Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL et al. Array-based genomic resequencing of human leukemia. Oncogene 2010; 29: 3723–3731.

    Article  CAS  PubMed  Google Scholar 

  27. Esteller M . Epigenetics in cancer. N Engl J Med 2008; 358: 1148–1159.

    Article  CAS  PubMed  Google Scholar 

  28. Jones PA, Baylin SB . The epigenomics of cancer. Cell 2007; 128: 683–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Thol F, Damm F, Ludeking A, Winschel C, Wagner K, Morgan M et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 2011; 29: 2889–2896.

    Article  CAS  PubMed  Google Scholar 

  30. Hou HA, Kuo YY, Liu CY, Chou WC, Lee MC, Chen CY et al. DNMT3A mutations in acute myeloid leukemia-stability during disease evolution and the clinical implication. Blood 2011; e-pub ahead of print 10 November 2011; doi:10.1182/blood-2011-07-369934.

    Article  PubMed  Google Scholar 

  31. Shen Y, Zhu YM, Fan X, Shi JY, Wang QR, Yan XJ et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood 2011; 118: 5593–5603.

    Article  CAS  PubMed  Google Scholar 

  32. Pautas C, Merabet F, Thomas X, Raffoux E, Gardin C, Corm S et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol 2010; 28: 808–814.

    Article  CAS  PubMed  Google Scholar 

  33. Thomas X, Raffoux E, Botton S, Pautas C, Arnaud P, de Revel T et al. Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group. Leukemia 2007; 21: 453–461.

    Article  CAS  PubMed  Google Scholar 

  34. International system for cytogenetic nomenclature: guidelines for cancer cytogenetics. In: Mitelmann F (ed). Supplement to an International System for Human Cytogenetic Nomenclature. S. Karger: Basel, Switzerland, 1995.

  35. Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, Kuriyama K et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia 1997; 11: 1447–1452.

    Article  CAS  PubMed  Google Scholar 

  36. Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT . Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 2001; 113: 983–988.

    Article  CAS  PubMed  Google Scholar 

  37. Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005; 106: 3618–3620.

    Article  CAS  PubMed  Google Scholar 

  38. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 2002; 100: 2717–2723.

    Article  CAS  PubMed  Google Scholar 

  39. Renneville A, Boissel N, Zurawski V, Llopis L, Biggio V, Nibourel O et al. Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. Cancer 2009; 115: 3719–3727.

    Article  CAS  PubMed  Google Scholar 

  40. Boissel N, Nibourel O, Renneville A, Gardin C, Reman O, Contentin N et al. Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol 2011; 28: 3717–3723.

    Article  Google Scholar 

  41. Boissel N, Nibourel O, Renneville A, Huchette P, Dombret H, Preudhomme C . Differential prognosis impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood 2011; 117: 3696–3697.

    Article  CAS  PubMed  Google Scholar 

  42. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  PubMed  Google Scholar 

  43. Ng PC, Henikoff S . SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 2003; 31: 3812–3814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Larochelle O, Bertoli S, Vergez F, Sarry JE, Mansat-De Mas V, Dobbelstein S et al. Do AML patients with DNMT3A exon 23 mutations benefit from idarubicin as compared to daunorubicin? A single center experience. Oncotarget 2011; 2: 850–861.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ho PA, Kutny MA, Alonzo TA, Gerbing RB, Joaquin J, Raimondi SC et al. Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: A report from the Children's Oncology Group. Pediatr Blood Cancer 2011; 57: 204–209.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Thol F, Heuser M, Damm F, Klusmann JH, Reinhardt K, Reinhardt D . DNMT3A mutations are rare in childhood acute myeloid leukemia. Haematologica 2011; 96: 1238–1240.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Shiba N, Taki T, Park MJ, Shimada A, Sotomatsu M, Adachi S et al. DNMT3A mutations are rare in childhood acute myeloid leukaemia, myelodysplastic syndromes and juvenile myelomonocytic leukaemia. Br J Haematol 2011; e-pub ahead of print 8 October 2011; doi: 10.1111/j.1365-2141.2011.08879.x.

    Article  PubMed  Google Scholar 

  48. Ehrlich M . The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin Immunol 2003; 109: 17–28.

    Article  CAS  PubMed  Google Scholar 

  49. Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999; 402: 187–191.

    Article  CAS  PubMed  Google Scholar 

  50. Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010; 17: 13–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Thol F, Damm F, Krauter J, Ganser A, Heuser M . Reply to S. Masuda. J Clin Oncol 2011; 29: 4593–4594.

    Article  Google Scholar 

  52. Stegelmann F, Bullinger L, Schlenk RF, Paschka P, Griesshammer M, Blersch C et al. DNMT3A mutations in myeloproliferative neoplasms. Leukemia 2011; 25: 1217–1219.

    Article  CAS  PubMed  Google Scholar 

  53. Walter MJ, Ding L, Shen D, Shao J, Grillot M, McLellan M et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 2011; 25: 1153–1158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Association Laurette Fugain, the Fondation de France (Leukemia Committee), the Ligue Contre le Cancer (North Center) and North-West Canceropole (Onco-Hematology axis), France.

Author information

Authors and Affiliations

  1. Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille, Lille, France

    A Renneville, O Nibourel, N Helevaut & C Preudhomme

  2. University of Lille Nord de France, Lille, France

    A Renneville, O Nibourel, C Berthon & C Preudhomme

  3. Inserm, U837, Team 3, Cancer Research Institute of Lille, Lille, France

    A Renneville, O Nibourel, C Berthon & C Preudhomme

  4. Department of Adult Hematology, Saint-Louis Hospital, EA 3518, University of Paris 7, APHP, Paris, France

    N Boissel & H Dombret

  5. Department of Hematology, Huriez Hospital, CHRU of Lille, Lille, France

    C Berthon

  6. Department of Hematology, Avicenne Hospital, APHP, Bobigny, France

    C Gardin & P Fenaux

  7. Laboratory of Hematology, Saint-Louis Hospital, APHP, Paris, France

    J-M Cayuela

  8. Laboratory of Molecular Biology and UMR5239 CNRS, Lyon Sud Hospital, Pierre-B, é, nite, France

    S Hayette

  9. Department of Hematology, Clemenceau Hospital, Caen, France

    O Reman

  10. Department of Hematology, Henri Becquerel Center, Rouen, France

    N Contentin

  11. Department of Hematology, Dupuytren Hospital, Limoges, France

    D Bordessoule

  12. Department of Hematology, Henri Mondor Hospital, APHP, Cr, é, teil, France

    C Pautas

  13. Department of Hematology, Gustave Roussy Institute, Villejuif, France

    S de Botton

  14. Department of Hematology, Hôpital des Arm,

    T de Revel

  15. é,

    T de Revel

  16. es, Clamart, France

    T de Revel

  17. Laboratory of Cytogenetics, Versailles Hospital, Le Chesnay, France

    C Terre

  18. Department of Hematology, Edouard Herriot Hospital, Lyon, France

    X Thomas

  19. Department of Hematology, Versailles Hospital, Le Chesnay, France

    S Castaigne

Authors
  1. A Renneville
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Boissel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O Nibourel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Berthon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Helevaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Gardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J-M Cayuela
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Hayette
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. O Reman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N Contentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Bordessoule
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C Pautas
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S de Botton
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T de Revel
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. C Terre
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. P Fenaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. X Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. S Castaigne
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. H Dombret
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. C Preudhomme
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Preudhomme.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Renneville, A., Boissel, N., Nibourel, O. et al. Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia 26, 1247–1254 (2012). https://doi.org/10.1038/leu.2011.382

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.382

Keywords

This article is cited by

Search

Advanced search

Quick links