Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study

J Clin Oncol. 2010 Feb 1;28(4):596-604. doi: 10.1200/JCO.2009.25.1496. Epub 2009 Dec 21.


Purpose: To analyze the prognostic significance of NPM1 mutations, and the associated gene- and microRNA-expression signatures in older patients with de novo, cytogenetically normal acute myeloid leukemia (CN-AML) treated with intensive chemotherapy.

Patients and methods: One hundred forty-eight adults age >or= 60 years with de novo CN-AML, enrolled onto Cancer and Leukemia Group B protocols 9720 and 10201, were studied at diagnosis for NPM1, FLT3, CEBPA, and WT1 mutations, and gene- and microRNA-expression profiles.

Results: Patients with NPM1 mutations (56%) had higher complete remission (CR) rates (84% v 48%; P < .001) and longer disease-free survival (DFS; P = .047; 3-year rates, 23% v 10%) and overall survival (OS; P < .001; 3-year rates, 35% v 8%) than NPM1 wild-type patients. In multivariable analyses, NPM1 mutations remained independent predictors for higher CR rates (P < .001) and longer DFS (P = .004) and OS (P < .001), after adjustment for other prognostic clinical and molecular variables. Unexpectedly, the prognostic impact of NPM1 mutations was mainly observed in patients >or= 70 years. Gene- and microRNA-expression profiles associated with NPM1 mutations were similar across older patient age groups and similar to those in younger (< 60 years) patients with CN-AML. These profiles were characterized by upregulation of HOX genes and their embedded microRNAs and downregulation of the prognostically adverse MN1, BAALC, and ERG genes.

Conclusion: NPM1 mutations have favorable prognostic impact in older patients with CN-AML, especially those age >or= 70 years. The gene- and microRNA-expression profiles suggest that NPM1 mutations constitute a marker defining a biologically homogeneous entity in CN-AML that might be treated with specific and/or targeted therapies across age groups.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • CCAAT-Enhancer-Binding Proteins / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Humans
  • Karyotyping
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Leukemia, Myeloid, Acute / therapy
  • Male
  • MicroRNAs / physiology*
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Staging
  • Nuclear Proteins / genetics*
  • Nucleophosmin
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Remission Induction
  • Survival Rate
  • Treatment Outcome
  • WT1 Proteins / genetics
  • fms-Like Tyrosine Kinase 3 / genetics


  • Biomarkers, Tumor
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • MicroRNAs
  • NPM1 protein, human
  • Nuclear Proteins
  • WT1 Proteins
  • Nucleophosmin
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3