title: Characterization of NPM1-mutated AML with a history of myelodysplastic syndromes or myeloproliferative neoplasms.
abstract: The role of the nucleophosmin (NPM1) mutations in de novo acute myeloid leukemia (AML) is well analyzed, but the impact in secondary AML (s-AML) following myelodysplastic syndromes (MDS) or transformed myeloproliferative neoplasms (MPNs) remains unclear. We investigated 350 patients-283 s-AML after MDS and 67 transformed MPNs-for NPM1mut. NPM1mut was detected in 43/350 patients (12.3%) at diagnosis of s-AML (transformed MDS: 37/283; 13.1%; transformed MPNs: 6/67; 9.0%). Cytogenetic alterations were present in 12/40 cases (30.0%) with available karyotypes. Additional molecular mutations were found in 23/43 NPM1mut s-AML after MDS (53.5%) and in transformed MPN in 18/37 (48.6%): FLT3-ITD: 14/37 (37.8%); FLT3-TKD: 3/28 (10.7%); NRASmut: 4/37 (10.8%), RUNX1mut: 1/16 (6.3%). In NPM1mut-transformed MPNs, five out of six cases showed 1-2 additional molecular mutations (2 × KITD816V, ETV6-PDGFRB, 2 × JAK2V617F, 2 × FLT3-ITD). Backtracking of nine of these cases by quantitative real time PCR showed the NPM1mut already at diagnosis of MDS/MPN, at variable levels and up to 14 months before diagnosis of AML, and at transformation often being preceded or accompanied by other genetic alterations. Thus, NPM1 mutations are involved in the transformation from MDS to AML or MPN to blast phase in single cases, which should be further confirmed in larger studies.
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany. susanne.schnittger@mll.com
authors.forename: S
authors.initials: S
authors.lastname: Schnittger
authors.forename: U
authors.initials: U
authors.lastname: Bacher
authors.forename: C
authors.initials: C
authors.lastname: Haferlach
authors.forename: T
authors.initials: T
authors.lastname: Alpermann
authors.forename: F
authors.initials: F
authors.lastname: Dicker
authors.forename: J
authors.initials: J
authors.lastname: Sundermann
authors.forename: W
authors.initials: W
authors.lastname: Kern
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001752:Blast Crisis; D002471:Cell Transformation, Neoplastic; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000401:mortality; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D016133:Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D004273:DNA, Neoplasm; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin