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.

  • Article
  • Published:

Mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia

Cancer Gene Therapy volume 25, pages 207–213 (2018)Cite this article

Subjects

Abstract

The mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML, are unclear. In order to explore the prognostic significance of the mutational spectrum in IR-AML, 106 IR-AML patients were collected from The Cancer Genome Atlas database. Sixty-two patients underwent chemotherapy-only, forty-four proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-five patients had more than five recurrent genetic mutations. NPM1 had the highest mutation frequency, followed by DNMT3A, FLT3, RUNX1, IDH2, IDH1, and TET2. In all patients, allo-HSCT was an independent favorable factor for EFS and OS (P = 0.036, P = 0.001, respectively); age ≥60 years, FLT3-ITD and mutations in DNMT3A and RUNX1 were independent risk factors for survival (all P < 0.05). In the chemotherapy-only group, multivariate analysis showed that age ≥60 years was an independent risk factor for EFS and OS (P = 0.008, P = 0.017, respectively). In the allo-HSCT group, multivariate analysis indicated that MLL-PTD was an independent risk fact for EFS (P = 0.037), FLT3-ITD and RUNX1 mutations independently contributed to poor OS (P = 0.035, P = 0.014, respectively). In conclusion, older age was an important risk factor for IR-AML patients undergoing chemotherapy-only; FLT3-ITD, MLL-PTD and RUNX1 mutations were significant risk factors for IR-AML patients who received allo-HSCT.

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

Fig. 1

Similar content being viewed by others

References

  1. Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14:275–91.

    Article  PubMed  CAS  Google Scholar 

  2. Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109:431–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 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;116:354–65.

    Article  PubMed  CAS  Google Scholar 

  4. 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;28:2739–47.

    Article  PubMed  CAS  Google Scholar 

  5. 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;117:2469–75.

    Article  PubMed  CAS  Google Scholar 

  6. Hou HA, Lin CC, Chou WC, Liu CY, Chen CY, Tang JL, et al. Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia. Leukemia. 2014;28:50–8.

    Article  PubMed  CAS  Google Scholar 

  7. Atallah E, Cortes J, O’Brien S, Pierce S, Rios MB, Estey E, et al. Establishment of baseline toxicity expectations with standard frontline chemotherapy in acute myelogenous leukemia. Blood. 2007;110:3547–51.

    Article  PubMed  CAS  Google Scholar 

  8. Estey EH. Acute myeloid leukemia: 2014 update on risk-stratification and management. Am J Hematol. 2014;89:1063–81.

    Article  PubMed  CAS  Google Scholar 

  9. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner 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;115:453–74.

    Article  PubMed  CAS  Google Scholar 

  10. Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhäuser M, Juliusson G, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9:579–90.

    Article  PubMed  CAS  Google Scholar 

  11. Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

    Article  PubMed  CAS  Google Scholar 

  12. Wang B, Liu Y, Hou G, Wang L, Lv N, Xu Y, et al. Mutational spectrum and risk stratification of intermediate-risk acute myeloid leukemia patients based on next-generation sequencing. Oncotarget. 2016;7:32065–78.

    PubMed  PubMed Central  Google Scholar 

  13. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

    Article  PubMed  CAS  Google Scholar 

  14. Kurosawa S, Yamaguchi T, Uchida N, Miyawaki S, Usuki K, Watanabe M, et al. Comparison of allogeneic hematopoietic cell transplantation and chemotherapy in elderly patients with non-M3 acute myelogenous leukemia in first complete remission. Biol Blood Marrow Transplant. 2011;17:401–11.

    Article  PubMed  Google Scholar 

  15. Metzelder SK, Schroeder T, Lübbert M, Ditschkowski M, Götze K, Scholl S, et al. Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation. Eur J Cancer. 2017;86:233–9.

    Article  PubMed  CAS  Google Scholar 

  16. Lin N, Fu W, Zhao C, Li B, Yan X, Li Y. Biologico-clinical significance of DNMT3A variants expression in acute myeloid leukemia. Biochem Biophys Res Commun. 2017;494:270–7.

    Article  PubMed  CAS  Google Scholar 

  17. Mendler JH, Maharry K, Radmacher MD, Mrózek K, Becker H, Metzeler KH, et al. RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures. J Clin Oncol. 2012;30:3109–18.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Schmid C, Labopin M, Socié G, Daguindau E, Volin L, Huynh A, et al. Outcome of patients with distinct molecular genotypes and cytogenetically normal AML after allogeneic transplantation. Blood. 2015;126:2062–9.

    Article  PubMed  CAS  Google Scholar 

  19. Luskin MR, Carroll M, Lieberman D, Morrissette JJD, Zhao J, Crisalli L, et al. Clinical utility of next-generation sequencing for oncogenic mutations in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22:1961–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ahn JS, Kim HJ, Kim YK, Lee SS, Jung SH, Yang DH, et al. DNMT3A R882 mutation with FLT3-ITD positivity is an extremely poor prognostic factor in patients with normal-karyotype acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22:61–70.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81500118, 61501519), the China Postdoctoral Science Foundation funded project (project No. 2016M600443), Jiangsu Province Postdoctoral Science Foundation funded project (project No. 1701184B) and PLAGH project of Medical Big Data (Project No. 2016MBD-025).

Author information

Author notes

  1. These authors contributed equally: Sun Wu, Yifeng Dai

  2. These authors jointly supervised this work: Jinlong Shi, Zhiheng Cheng, Lin Fu

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China

    Sun Wu, Yuan Zhang, Xiufeng Wang, Lihua Wang, Dong Ma & Lingxiu Zhang

  2. Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, Shantou, 515041, China

    Yifeng Dai

  3. Department of Pathology and Medical Biology, Immunoendocrinology, Division of Medical Biology, University Medical Center Groningen, Groningen, Netherlands

    Yifeng Dai

  4. Department of Medicine, William Beaumont Hospital, Royal Oak, MI, 48073, USA

    Yifan Pang

  5. Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, 310058, China

    Yang Jiao

  6. Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

    Mingshan Niu, Kailin Xu & Lin Fu

  7. Department of Hematology and Lymphoma Research Center, Peking University, Third Hospital, Beijing, 100191, China

    Xiaoyan Ke & Lin Fu

  8. Translational Medicine Center, Huaihe Hospital of Henan University, Kaifeng, 475000, China

    Jinlong Shi & Zhiheng Cheng

  9. Department of Biomedical Engineering, Chinese PLA General Hospital, Beijing, 100853, China

    Jinlong Shi

  10. Department of Medical Big Data, Chinese PLA General Hospital, Beijing, 100853, China

    Jinlong Shi

  11. Department of Hematology, Huaihe Hospital of Henan University, Kaifeng, 475000, China

    Lin Fu

Authors
  1. Sun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yifeng Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiufeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lihua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lingxiu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yifan Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yang Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mingshan Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kailin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiaoyan Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jinlong Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Zhiheng Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Lin Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhiheng Cheng.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, S., Dai, Y., Zhang, Y. et al. Mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia. Cancer Gene Ther 25, 207–213 (2018). https://doi.org/10.1038/s41417-018-0028-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-018-0028-z

This article is cited by

Search

Advanced search

Quick links