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.
journal_name
Bloodjournal_title
Bloodauthors
Krönke J,Bullinger L,Teleanu V,Tschürtz F,Gaidzik VI,Kühn MW,Rücker FG,Holzmann K,Paschka P,Kapp-Schwörer S,Späth D,Kindler T,Schittenhelm M,Krauter J,Ganser A,Göhring G,Schlegelberger B,Schlenk RF,Döhner H,Döhner Kdoi
10.1182/blood-2013-01-479188subject
Has Abstractpub_date
2013-07-04 00:00:00pages
100-8issue
1eissn
0006-4971issn
1528-0020pii
blood-2013-01-479188journal_volume
122pub_type
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