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: Jan Krönke, Lars Bullinger, Veronica Teleanu, Florian Tschürtz, Verena I Gaidzik, Michael W M Kühn, Frank G Rücker, Karlheinz Holzmann, Peter Paschka, Silke Kapp-Schwörer, Daniela Späth, Thomas Kindler, Marcus Schittenhelm, Jürgen Krauter, Arnold Ganser, Gudrun Göhring, Brigitte Schlegelberger, Richard F Schlenk, Hartmut Döhner, Konstanze Döhner
• Journal: Blood (Blood) Vol. 122 Issue 1 Pg. 100-8 (Jul 04 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23704090 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNMT3A protein, human
• NPM1 protein, human
• Nuclear Proteins
• Nucleophosmin
• DNA (Cytosine-5-)-Methyltransferases
• DNA Methyltransferase 3A

Topics

• Adult
• Aged
• Chromosomes, Human, Pair 13
• Chromosomes, Human, Pair 9
• Clonal Evolution (genetics)
• DNA (Cytosine-5-)-Methyltransferases (genetics)
• DNA Fingerprinting
• DNA Methyltransferase 3A
• Female
• Gene Deletion
• Humans
• Leukemia, Myeloid, Acute (diagnosis, epidemiology, genetics)
• Male
• Middle Aged
• Nuclear Proteins (genetics)
• Nucleophosmin
• Polymorphism, Single Nucleotide (genetics)
• Prognosis
• Recurrence
• Risk Factors
• Young Adult