title: Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia.
abstract: Mutations in the nucleophosmin 1 (NPM1) gene are considered a founder event in the pathogenesis of acute myeloid leukemia (AML). To address the role of clonal evolution in relapsed NPM1-mutated (NPM1mut) AML, we applied high-resolution, genome-wide, single-nucleotide polymorphism array profiling to detect copy number alterations (CNAs) and uniparental disomies (UPDs) and performed comprehensive gene mutation screening in 53 paired bone marrow/peripheral blood samples obtained at diagnosis and relapse. At diagnosis, 15 aberrations (CNAs, n = 10; UPDs, n = 5) were identified in 13 patients (25%), whereas at relapse, 56 genomic alterations (CNAs, n = 46; UPDs, n = 10) were detected in 29 patients (55%) indicating an increase in genomic complexity. Recurrent aberrations acquired at relapse included deletions affecting tumor suppressor genes (ETV6 [n = 3], TP53 [n = 2], NF1 [n = 2], WT1 [n = 3], FHIT [n = 2]) and homozygous FLT3 mutations acquired via UPD13q (n = 7). DNMT3A mutations (DNMT3Amut) showed the highest stability (97%). Persistence of DNMT3Amut in 5 patients who lost NPM1mut at relapse suggests that DNMT3Amut may precede NPM1mut in AML pathogenesis. Of note, all relapse samples shared at least 1 genetic aberration with the matched primary AML sample, implying common ancestral clones. In conclusion, our study reveals novel insights into clonal evolution in NPM1mut AML.
authors.affiliation: Department of Internal Medicine III, Genomics Core Facility, University of Ulm, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Krönke
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Veronica
authors.initials: V
authors.lastname: Teleanu
authors.forename: Florian
authors.initials: F
authors.lastname: Tschürtz
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.forename: Michael W M
authors.initials: MW
authors.lastname: Kühn
authors.forename: Frank G
authors.initials: FG
authors.lastname: Rücker
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Holzmann
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Silke
authors.initials: S
authors.lastname: Kapp-Schwörer
authors.forename: Daniela
authors.initials: D
authors.lastname: Späth
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.forename: Marcus
authors.initials: M
authors.lastname: Schittenhelm
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000328:Adult; D000368:Aged; D002882:Chromosomes, Human, Pair 13; D002899:Chromosomes, Human, Pair 9; D060965:Clonal Evolution / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D016172:DNA Fingerprinting; D000090205:DNA Methyltransferase 3A; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D012008:Recurrence; D012307:Risk Factors; D055815:Young Adult
chemical_list: C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A