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Microarray Gene Expression Profiling of B-Cell Chronic Lymphocytic Leukemia Subgroups Defined by Genomic Aberrations and VH Mutation Status

From the Department of Lead Discovery, Boehringer Ingelheim Austria, Vienna, Austria; Department of Internal Medicine III, University of Ulm, Ulm; Division of Molecular Genetics, German Cancer Research Center, Heidelberg; Institute of Computer Science, Ludwig-Maximilians-Universität, Munich, Germany.

Address reprint requests to Christian Stratowa, PhD, Department of Lead Discovery, Boehringer Ingelheim Austria, Dr Boehringer-Gasse 5-11, A-1121 Vienna, Austria; e-mail: christian.stratowa{at}vie.boehringer-ingelheim.com

PURPOSE: Genomic aberrations and mutational status of the immunoglobulin variable heavy chain (VH) gene have been shown to be among the most important predictors for outcome in patients with B-cell chronic lymphocytic leukemia (B-CLL). In this study, we report on differential gene expression patterns that are characteristic for genetically defined B-CLL subtypes.

MATERIALS AND METHODS: One hundred genetically well-characterized B-CLL samples, together with 11 healthy control samples, were analyzed using oligonucleotide arrays, which test for the expression of some 12,000 human genes.

RESULTS: Aiming at microarray-based subclassification, class predictors were constructed using sets of differentially expressed genes, which yielded in zero or low misclassification rates. Furthermore, a significant number of the differentially expressed genes clustered in chromosomal regions affected by the respective genomic losses/gains. Deletions affecting chromosome bands 11q22-q23 and 17p13 led to a reduced expression of the corresponding genes, such as ATM and p53, while trisomy 12 resulted in the upregulation of genes mapping to chromosome arm 12q. Using an unsupervised analysis algorithm, expression profiling allowed partitioning into predominantly VH-mutated versus unmutated patient groups; however, association of the expression profile with the VH mutational status could only be detected in male patients.

CONCLUSION: The finding that the most significantly differentially expressed genes are located in the corresponding aberrant chromosomal regions indicates that a gene dosage effect may exert a pathogenic role in B-CLL. The significant difference in the partitioning of male and female B-CLL samples suggests that the genomic signature for the VH mutational status might be sex-related.

Supported by grant 01KW9936 within the German Human Genome Project funded by the German Federal Ministry of Education and Research.

Presented at EuroBiochips 2003, London, England, May 20-23, 2003.

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

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