Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia

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Item Type:	Article
Title:	Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia
Creators Name:	Krönke, J., Bullinger, L., Teleanu, V., Tschürtz, F., Gaidzik, V.I., Kühn, M.W.M., Rücker, F.G., Holzmann, K., Paschka, P., Kapp-Schwörer, S., Späth, D., Kindler, T., Schittenhelm, M., Krauter, J., Ganser, A., Göhring, G., Schlegelberger, B., Schlenk, R.F., Döhner, H. and Döhner, K.
Abstract:	(mut)ations 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-(mut)ated (NPM1(mut)) 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 (mut)ation 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 (mut)ations acquired via UPD13q (n = 7). DNMT3A (mut)ations (DNMT3A(mut)) showed the highest stability (97%). Persistence of DNMT3A(mut) in 5 patients who lost NPM1(mut) at relapse suggests that DNMT3A(mut) may precede NPM1(mut) 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 NPM1(mut) AML.
Keywords:	Acute Myeloid Leukemia, Clonal Evolution, DNA (Cytosine-5-)-Methyltransferases, DNA Fingerprinting, DNA Methyltransferase 3A, Gene Deletion, Nuclear Proteins, Nucleophosmin, Pair 13 Human Chromosomes, Pair 9 Human Chromosomes, Prognosis, Recurrence, Risk Factors, Single Nucleotide Polymorphism, Young Adult
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	122
Number:	1
Page Range:	100-108
Date:	4 July 2013
Official Publication:	https://doi.org/10.1182/blood-2013-01-479188
PubMed:	View item in PubMed

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