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 myeloid leukemia

Copy-number analysis identified new prognostic marker in acute myeloid leukemia

Abstract

Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Mrozek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol 2012; 30: 4515–4523.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rollig C, Bornhauser M, Thiede C, Taube F, Kramer M, Mohr B et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol 2011; 29: 2758–2765.

    Article  PubMed  Google Scholar 

  3. Vardiman JW, Harris NL, Brunning RD . The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100: 2292–2302.

    Article  CAS  PubMed  Google Scholar 

  4. 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 2010; 115: 453–474.

    Article  PubMed  Google Scholar 

  5. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B et al. Pan-cancer patterns of somatic copy number alteration. Nat Genet 2013; 45: 1134–1140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360: 470–480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.

    Article  CAS  PubMed  Google Scholar 

  9. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Google Scholar 

  10. 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 

  11. Thomas X, Elhamri M, Raffoux E, Renneville A, Pautas C, de BS et al. Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study. Blood 2011; 118: 1754–1762.

    Article  CAS  PubMed  Google Scholar 

  12. Castaigne S, Pautas C, Terre C, Raffoux E, Bordessoule D, Bastie JN et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 2012; 379: 1508–1516.

    Article  CAS  PubMed  Google Scholar 

  13. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  14. Shaffer LG, Tommerup N, Slovak ML, Campbell L ISCN 2009: International System for Human Cytogenetic Nomenclature 2009 Karger; Basel, Switzerland, 2009.

  15. Renneville A, Abdelali RB, Chevret S, Nibourel O, Cheok M, Pautas C et al. Clinical impact of gene mutations and lesions detected by SNP-array karyotyping in acute myeloid leukemia patients in the context of gemtuzumab ozogamicin treatment: results of the ALFA-0701 trial. Oncotarget 2014; 5: 916–932.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lambert J, Lambert J, Nibourel O, Pautas C, Hayette S, Cayuela JM et al. MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin. Oncotarget 2014; 5: 6280–6288.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Renneville A, Boissel N, Nibourel O, Berthon C, Helevaut N, Gardin C et al. Prognostic significance of DNA methyltransferase 3 A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia 2012; 26: 1247–1254.

    Article  CAS  PubMed  Google Scholar 

  18. Abdelhamid E, Figeac M, Renneville A, Quief S, Villenet C, Boyer T et al. Quantification of JAK2V617F mutation by next-generation sequencing technology. Am J Hematol 2013; 88: 536–537.

    Article  CAS  PubMed  Google Scholar 

  19. Holleman A, Cheok MH, den Boer ML, Yang W, Veerman AJ, Kazemier KM et al. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med 2004; 351: 533–542.

    Article  CAS  PubMed  Google Scholar 

  20. Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D et al. Circos: an information aesthetic for comparative genomics. Genome Res 2009; 19: 1639–1645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Parkin B, Ouillette P, Yildiz M, Saiya-Cork K, Shedden K, Malek SN . Integrated genomic profiling, therapy response, and survival in adult acute myelogenous leukemia. Clin Cancer Res 2015; 21: 2045–2056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tiu RV, Gondek LP, O'Keefe CL, Elson P, Huh J, Mohamedali A et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011; 117: 4552–4560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Walter MJ, Payton JE, Ries RE, Shannon WD, Deshmukh H, Zhao Y et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci USA 2009; 106: 12950–12955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rucker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012; 119: 2114–2121.

    Article  PubMed  Google Scholar 

  25. Parkin B, Erba H, Ouillette P, Roulston D, Purkayastha A, Karp J et al. Acquired genomic copy number aberrations and survival in adult acute myelogenous leukemia. Blood 2010; 116: 4958–4967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yi JH, Huh J, Kim HJ, Kim SH, Kim HJ, Kim YK et al. Adverse prognostic impact of abnormal lesions detected by genome-wide single nucleotide polymorphism array-based karyotyping analysis in acute myeloid leukemia with normal karyotype. J Clin Oncol 2011; 29: 4702–4708.

    Article  PubMed  Google Scholar 

  27. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hieronymus H, Schultz N, Gopalan A, Carver BS, Chang MT, Xiao Y et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci USA 2014; 111: 11139–11144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Moorman AV, Enshaei A, Schwab C, Wade R, Chilton L, Elliott A et al. A novel integrated cytogenetic and genomic classification refines risk stratification in pediatric acute lymphoblastic leukemia. Blood 2014; 124: 1434–1444.

    Article  CAS  PubMed  Google Scholar 

  30. Harris MH, DuBois SG, Glade Bender JL, Kim A, Crompton BD, Parker E et al. Multicenter feasibility study of tumor molecular profiling to inform therapeutic decisions in advanced pediatric solid tumors: the individualized cancer therapy (iCat) study. JAMA Oncol 2016; 2: 608–615.

    Article  PubMed  Google Scholar 

  31. Wang GG, Cai L, Pasillas MP, Kamps MP . NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 2007; 9: 804–812.

    Article  CAS  PubMed  Google Scholar 

  32. Sarova I, Brezinova J, Zemanova Z, Bystricka D, Krejcik Z, Soukup P et al. Characterization of chromosome 11 breakpoints and the areas of deletion and amplification in patients with newly diagnosed acute myeloid leukemia. Genes Chromosomes Cancer 2013; 52: 619–635.

    Article  CAS  PubMed  Google Scholar 

  33. Martens JH . Acute myeloid leukemia: a central role for the ETS factor ERG. Int J Biochem Cell Biol 2011; 43: 1413–1416.

    Article  CAS  PubMed  Google Scholar 

  34. Marcucci G, Baldus CD, Ruppert AS, Radmacher MD, Mrozek K, Whitman SP et al. Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. J Clin Oncol 2005; 23: 9234–9242.

    Article  CAS  PubMed  Google Scholar 

  35. Metzeler KH, Dufour A, Benthaus T, Hummel M, Sauerland MC, Heinecke A et al. ERG expression is an independent prognostic factor and allows refined risk stratification in cytogenetically normal acute myeloid leukemia: a comprehensive analysis of ERG, MN1, and BAALC transcript levels using oligonucleotide microarrays. J Clin Oncol 2009; 27: 5031–5038.

    Article  CAS  PubMed  Google Scholar 

  36. Baldus CD, Liyanarachchi S, Mrozek K, Auer H, Tanner SM, Guimond M et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA 2004; 101: 3915–3920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rucker FG, Bullinger L, Schwaenen C, Lipka DB, Wessendorf S, Frohling S et al. Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization. J Clin Oncol 2006; 24: 3887–3894.

    Article  PubMed  Google Scholar 

  38. Tursky ML, Beck D, Thoms JA, Huang Y, Kumari A, Unnikrishnan A et al. Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias. Leukemia 2015; 29: 819–827.

    Article  CAS  PubMed  Google Scholar 

  39. Zong Y, Xin L, Goldstein AS, Lawson DA, Teitell MA, Witte ON . ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells. Proc Natl Acad Sci USA 2009; 106: 12465–12470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Willemze R, Suciu S, Meloni G, Labar B, Marie JP, Halkes CJ et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol 2014; 32: 219–228.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all medical staff and patients participating in the Acute Leukemia French Association protocols; and Cécile Frimat for data management support. The results of the TCGA data presented here are based wholly or partly upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This work was supported by the French Association Laurette Fugain, Fondation de France (Leukemia Committee), LigueContre le Cancer (North Center), Canceropole NO (Onco-Hematology axis), SIRIC Oncolille, French National Cancer Institute (translational research acronyms: DREAM and PLP bio AML project) and Cancéropôle PACA and France Génomique, Labex Signalife.

Author contributions

Conception and design: BQ, SC, HD, JS, CP and MHC. Administrative support and clinical data management: CD, KC-L, HD and CP. Study material and clinical analyses: CR, CT, BQ, SC and HD. Data acquisition and analysis: ON, SG, AP, CR, CT, PP, SG, RBA, AR, PB, CP and MHC. All authors participated in the manuscript preparation and the final review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M H Cheok.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nibourel, O., Guihard, S., Roumier, C. et al. Copy-number analysis identified new prognostic marker in acute myeloid leukemia. Leukemia 31, 555–564 (2017). https://doi.org/10.1038/leu.2016.265

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.265

This article is cited by

Search

Quick links