title: Prognostic significance of NPM1 mutation-modulated microRNA-mRNA regulation in acute myeloid leukemia.
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.
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.|Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chiu
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.|Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.|Center for Biotechnology, National Taiwan University, Taipei, Taiwan.|Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: M-H
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Kuo
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: H-A
authors.initials: HA
authors.lastname: Hou
authors.affiliation: Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: T-P
authors.initials: TP
authors.lastname: Lu
authors.affiliation: Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan.
authors.forename: L-C
authors.initials: LC
authors.lastname: Lai
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: H-F
authors.initials: HF
authors.lastname: Tien
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.|Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.|Center for Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: E Y
authors.initials: EY
authors.lastname: Chuang
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D035683:MicroRNAs / Q000032:analysis*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis*
chemical_list: D035683:MicroRNAs; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000090243:Nucleophosmin