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Acute myeloid leukemia

Prognostic significance of NPM1 mutation-modulated microRNA−mRNA regulation in acute myeloid leukemia

Leukemia volume 30, pages 274–284 (2016)Cite this article

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Abstract

Distinct microRNA (miRNA) and mRNA signatures were reported in nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML). However, it remains unknown whether the mutation participates in the dynamic interaction between miRNA and mRNA. In this study, we aimed to investigate the role of NPM1 mutation in modulating miRNA–mRNA regulation (MMR). From the sample-paired miRNA/mRNA microarrays of 181 de novo AML patients, we found that MMR was dynamic and could be affected by NPM1 mutation. By a systematic framework, we identified 493 NPM1 mutation-modulated MMR pairs, where the strength of MMR was significantly attenuated in patients carrying NPM1 mutations, compared to those with wild-type NPM1. These miRNAs/mRNAs were associated with pathways implicated in cancer and known functions of NPM1 mutation. Such modulation of MMR was validated in two independent cohorts as well as in cells with different NPM1 mutant burdens. Furthermore, we showed that the regulatory strength of nine MMR pairs could predict patients’ outcomes. Combining these pairs, a scoring system was proposed and shown to predict survival in discovery and validation data sets, independent of other known prognostic factors. Our study provides novel biological insights into the role of NPM1 mutation as a modulator of MMR, based on which a novel prognostic marker is proposed in AML.

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Acknowledgements

The study was supported by a National Taiwan University Hospital−National Taiwan University joint research grant (UN103-051), Ministry of Science and Technology of Taiwan (MOST102-2325-B-002-028, 103-2314-B-002-130-MY3, 103-2314-B-002-131-MY3, 103-2314-B-002-034-MY3, 103-2320-B-002-065-MY3, 104-2311-B-002-030 and 104-2923-B-002-001), and Ministry of Health and Welfare of Taiwan (MOHW102-TD-C-111-001 and MOHW103-TD-B-111-04). We thank the NTU Center of Genomic Medicine, National Taiwan University, for providing financial support (104R8400) and computing facilities. We also thank Mark D Minden, MD PhD, from Princess Margaret Hospital, Toronto, Canada, for kindly providing the OCI/AML3 cell line and Melissa Stauffer, PhD, of Scientific Editing Solutions, for editing the manuscript.

Author contributions

YCC, MHT, WCC, HFT and EYC conceived the study together. WCC, HAH and HFT prepared and provided the NTUH data sets. YCC designed the analysis framework, collected the TCGA data sets and carried out the data analyses. YCC, MHT, WCC, YCL, YYK and EYC designed, and YCL and YYK performed the in vitro experiments. YCC, MHT, WCC, YCL and EYC participated in data interpretation. TPL, LCL and YC contributed important materials and help to the study. YCC drafted the manuscript. MHT, WCC, HFT and EYC revised the manuscript. All authors read and approved the final manuscript.

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Author notes

  1. Y-C Chiu, M-H Tsai and W-C Chou: These authors contributed equally to this work.

Authors and Affiliations

  1. Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan

    Y-C Chiu, Y-C Liu & E Y Chuang

  2. Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Y-C Chiu & Y Chen

  3. Institute of Biotechnology, National Taiwan University, Taipei, Taiwan

    M-H Tsai

  4. Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan

    M-H Tsai, L-C Lai & E Y Chuang

  5. Center for Biotechnology, National Taiwan University, Taipei, Taiwan

    M-H Tsai & E Y Chuang

  6. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan

    M-H Tsai

  7. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

    W-C Chou & Y-Y Kuo

  8. Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    W-C Chou, H-A Hou & H-F Tien

  9. Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan

    T-P Lu

  10. Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan

    L-C Lai

  11. Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Y Chen

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  1. Y-C Chiu
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Correspondence to H-F Tien or E Y Chuang.

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Chiu, YC., Tsai, MH., Chou, WC. et al. Prognostic significance of NPM1 mutation-modulated microRNA−mRNA regulation in acute myeloid leukemia. Leukemia 30, 274–284 (2016). https://doi.org/10.1038/leu.2015.253

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