Originally published as JCO Early Release 10.1200/JCO.2005.04.5450 on July 24 2006

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Disclosure of Candidate Genes in Acute Myeloid Leukemia With Complex Karyotypes Using Microarray-Based Molecular Characterization

Frank G. Rücker, Lars Bullinger, Carsten Schwaenen, Daniel B. Lipka, Swen Wessendorf, Stefan Fröhling, Martin Bentz, Simone Miller, Claudia Scholl, Richard F. Schlenk, Bernhard Radlwimmer, Hans A. Kestler, Jonathan R. Pollack, Peter Lichter, Konstanze Döhner, Hartmut Döhner

From the Department of Neural Information Processing; Department of Internal Medicine III, University Hospital of Ulm, Ulm; Department of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany; and the Department of Pathology, Stanford University, Stanford, CA

Address reprint requests to Hartmut Döhner, MD, Department of Internal Medicine III, University Hospital of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany; e-mail: hartmut.doehner{at}uniklinik-ulm.de

PURPOSE: To identify novel genomic regions of interest in acute myeloid leukemia (AML) with complex karyotypes, we applied comparative genomic hybridization to microarrays (array-CGH), allowing high-resolution genome-wide screening of genomic imbalances.

PATIENTS AND METHODS: Sixty AML cases with complex karyotypes were analyzed using array-CGH; parallel analysis of gene expression was performed in a subset of cases.

RESULTS: Genomic losses were found more frequently than gains. The most frequent losses affected 5q (77%), 17p (55%), and 7q (45%), and the most frequent genomic gains 11q (40%) and 8q (38%). Critical segments could be delineated to genomic fragments of only 0.8 to a few megabase-pairs of DNA. In lost/gained regions, gene expression profiling detected a gene dosage effect with significant lower/higher average gene expression levels across the genes located in the respective regions. Furthermore, high-level DNA amplifications were identified in several regions: 11q23.3-q24.1 (n = 7), 21q22 (n = 6), 11q23.3 (n = 5), 13q12 (n = 3), 8q24 (n = 3), 9p24 (n = 2), 12p13 (n = 2), and 20q11 (n = 2). Parallel analysis of gene expression in critical amplicons displayed overexpressed candidate genes (eg, C8FW and MYC in 8q24).

CONCLUSION: In conclusion, a large spectrum of genomic imbalances, including novel recurring changes in AML with complex karyotypes, was identified using array-CGH. In addition, the combined analysis of array-CGH data with gene expression profiles allowed the detection of candidate genes involved in the pathogenesis of AML.

published online ahead of print at www.jco.org on July 24, 2006.

Supported by Bundesministerium für Bildung und Forschung (BMBF), Grant No. 01GS0439 NGFN2.

Presented in part at Gemeinsame Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaft für Hämatologie und Onkologie, Innsbruck, Austria, October 2-6, 2002; Gemeinsame Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaft für Hämatologie und Onkologie, Hannover, Germany, October 1-5, 2005; 10th Congress of the European Hematology Associate, Stockholm, Sweden, June 2-5, 2005; and the 26th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004.

F.G.R. and L.B. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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