title: NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features.
abstract: Frameshift mutations of the nucleophosmin gene (NPM1) were recently reported as a frequently occurring abnormality in patients with de novo acute myeloid leukemia (AML). To evaluate the frequency of NPM1 mutations in patients with therapy-related myelodysplasia (t-MDS) and therapy-related AML (t-AML), and their possible association to type of previous therapy and to other gene mutations, 140 patients with t-MDS or t-AML were analyzed for mutations of NPM1. NPM1 mutations were observed in 7 of 51 patients presenting as overt t-AML, as compared to only 3 of 89 patients presenting as t-MDS (P=0.037). The mutations were not related to any specific type of previous therapy, but they were significantly associated with a normal karyotype and mutations of FLT3 (P=0.0002 for both comparisons). Only 1 of 10 patients with NPM1 mutations presented chromosome aberrations characteristic of therapy-related disease, and 7q-/-7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P=0.002). This raises the question whether some of the cases presenting NPM1 mutations were in fact cases of de novo leukemia. The close association to class I mutations and the inverse association to class II mutations suggest mutations of NPM1 as representing a class II mutation-like abnormality in AML.
authors.affiliation: Department of Clinical Genetics, Hematology/Oncology Section 4052, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. morten.tolstrup.andersen@rh.regionh.dk
authors.forename: M T
authors.initials: MT
authors.lastname: Andersen
authors.forename: M K
authors.initials: MK
authors.lastname: Andersen
authors.forename: D H
authors.initials: DH
authors.lastname: Christiansen
authors.forename: J
authors.initials: J
authors.lastname: Pedersen-Bjergaard
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D003951:Diagnostic Errors; D005260:Female; D005787:Gene Frequency; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D050505:Mutant Proteins; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000175:diagnosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D050505:Mutant Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D051941:fms-Like Tyrosine Kinase 3