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Acute Leukemias

Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis

Leukemia volume 24, pages 438–449 (2010)Cite this article

Abstract

Recent advances in genome-wide single-nucleotide polymorphism (SNP) analyses have revealed previously unrecognized microdeletions and uniparental disomy (UPD) in a broad spectrum of human cancers. As acute myeloid leukemia (AML) represents a genetically heterogeneous disease, this technology might prove helpful, especially for cytogenetically normal AML (CN-AML) cases. Thus, we performed high-resolution SNP analyses in 157 adult cases of CN-AML. Regions of acquired UPDs were identified in 12% of cases and in the most frequently affected chromosomes, 6p, 11p and 13q. Notably, acquired UPD was invariably associated with mutations in nucleophosmin 1 (NPM1) or CCAAT/enhancer binding protein-α (CEBPA) that impair hematopoietic differentiation (P=0.008), suggesting that UPDs may preferentially target genes that are essential for proliferation and survival of hematopoietic progenitors. Acquired copy number alterations (CNAs) were detected in 49% of cases with losses found in two or more cases affecting, for example, chromosome bands 3p13–p14.1 and 12p13. Furthermore, we identified two cases with a cryptic t(6;11) as well as several non-recurrent aberrations pointing to leukemia-relevant regions. With regard to clinical outcome, there seemed to be an association between UPD 11p and UPD 13q cases with overall survival. These data show the potential of high-resolution SNP analysis for identifying genomic regions of potential pathogenic and clinical relevance in AML.

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Acknowledgements

For excellent technical assistance we thank Karina Eiwen, Sabrina Heinrich, Marianne Habdank, Karin Lanz and Simone Miller. Thanks also to Dr Jing Ma und Dr Xiaoping Su for their help with data analysis, and we thank all the members of the German-Austrian AMLSG for their participation in the clinical trials and for providing leukemia samples. This study was supported in part by the Deutsche Forschungsgemeinschaft (SCHO 1296/1-1), the Else Kröner-Fresenius-Stiftung (P32/2004) and the American Lebanese and Syrian Associated Charities (ALSAC) of St Jude Children's Research Hospital. Lars Bullinger designed and performed the research, analyzed/interpreted the data and wrote the paper; Jan Krönke performed the research and analyzed/interpreted the data; Christian Schön performed the research and analyzed/interpreted the data; Ina Radtke analyzed/interpreted the data; Katja Urlbauer performed the research and analyzed the data; Ursula Botzenhardt, Verena Gaidzik, Ana Carió and Christine Senger performed the research; Richard F Schlenk analyzed/interpreted the data; James R Downing contributed the analytical tools and analyzed/interpreted the data; Karlheinz Holzmann designed and performed the research and analyzed/interpreted the data; Konstanze Döhner designed the research, analyzed/interpreted the data and wrote the paper; Hartmut Döhner designed the research, contributed vital reagents, analyzed/interpreted the data and wrote the paper.

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Author notes

  1. L Bullinger, J Krönke and C Schön: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    L Bullinger, J Krönke, C Schön, K Urlbauer, U Botzenhardt, V Gaidzik, A Carió, C Senger, R F Schlenk, K Döhner & H Döhner

  2. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA

    I Radtke & J R Downing

  3. Microarray Core Facility, University of Ulm, Ulm, Germany

    K Holzmann

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Bullinger, L., Krönke, J., Schön, C. et al. Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis. Leukemia 24, 438–449 (2010). https://doi.org/10.1038/leu.2009.263

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