title: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations.
abstract: To assess the prognostic relevance of mutations in the NPM1 gene encoding a nucleocytoplasmic shuttle protein in younger adults with acute myeloid leukemia (AML) and normal cytogenetics, sequencing of NPM1 exon 12 was performed in diagnostic samples from 300 patients entered into 2 consecutive multicenter trials of the AML Study Group (AMLSG). Treatment included intensive double-induction therapy and consolidation therapy with high cumulative doses of high-dose cytarabine. NPM1 mutations were identified in 48% of the patients including 12 novel sequence variants, all leading to a frameshift in the C-terminus of the nucleophosmin 1 (NPM1) protein. Mutant NPM1 was associated with specific clinical, phenotypical, and genetic features. Statistical analysis revealed a significant interaction of NPM1 and FLT3 internal tandem duplications (ITDs). NPM1 mutations predicted for better response to induction therapy and for favorable overall survival (OS) only in the absence of FLT3 ITD. Multivariable analysis for OS revealed combined NPM1-mutated/FLT3 ITD-negative status, CEBPA mutation status, availability of a human leukocyte antigen (HLA)-compatible donor, secondary AML, and lactate dehydrogenase (LDH) as prognostic factors. In conclusion, NPM1 mutations in the absence of FLT3 ITD define a distinct molecular and prognostic subclass of young-adult AML patients with normal cytogenetics.
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Robert-Koch-Str 8, 89081 Ulm, Germany. konstanze.doehner@medizin.uni-ulm.de
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Marianne
authors.initials: M
authors.lastname: Habdank
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.forename: Frank G
authors.initials: FG
authors.lastname: Rücker
authors.forename: Andrea
authors.initials: A
authors.lastname: Corbacioglu
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000235:genetics; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016019:Survival Analysis; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D023081:CCAAT-Binding Factor; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3