title: Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML).
abstract: Mutations of the nucleophosmin (NPM1) gene have recently been described in patients with acute myeloid leukemia (AML). To clarify the prevalence as well as the clinical impact of this mutation, we investigated 1485 patients with AML for NPM1 exon 12 mutations using fragment analysis. A 4 bp insert was detected in 408 of 1485 patients (27.5%). Sequence analysis revealed known mutations (type A, B, and D) as well as 13 novel alterations in 229 analyzed cases. NPM1 mutations were most prevalent in patients with normal karyotype (NK) (324 of 709; 45.7%) compared with 58 of 686 with karyotype abnormalities (8.5%; P < .001) and were significantly associated with several clinical parameters (high bone marrow [BM] blasts, high white blood cell [WBC] and platelet counts, female sex). NPM1 alterations were associated with FLT3-ITD mutations, even if restricted to patients with NK (NPM1-mut/FLT3-ITD: 43.8%; versus NPM1-wt/FLT3-ITD: 19.9%; P < .001). The analysis of the clinical impact in 4 groups (NPM1 and FLT3-ITD single mutants, double mutants, and wild-type [wt] for both) revealed that patients having only an NPM1 mutation had a significantly better overall and disease-free survival and a lower cumulative incidence of relapse. In conclusion, NPM1 mutations represent a common genetic abnormality in adult AML. If not associated with FLT3-ITD mutations, mutant NPM1 appears to identify patients with improved response toward treatment.
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der Technischen Universität, Fetscherstrasse 74, 01307 Dresden, Germany. thiede@mk1.med.tu-dresden.de
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Sina
authors.initials: S
authors.lastname: Koch
authors.forename: Eva
authors.initials: E
authors.lastname: Creutzig
authors.forename: Christine
authors.initials: C
authors.lastname: Steudel
authors.forename: Thomas
authors.initials: T
authors.lastname: Illmer
authors.forename: Markus
authors.initials: M
authors.lastname: Schaich
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D004251:DNA Transposable Elements; D005091:Exons; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D016133:Polymerase Chain Reaction; D015995:Prevalence; D011379:Prognosis
chemical_list: D004251:DNA Transposable Elements; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin