1. ¹Department of Hematology–Oncology, St Jude Children's Research Hospital, Memphis, TN, USA
2. ²Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA
3. ³Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA
4. ⁴Hartwell Center for Bioinformatics and Biotechnology, St Jude Children's Research Hospital, Memphis, TN, USA
5. ⁵Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA
6. ⁶University of Tennessee, Memphis, TN, USA
7. ⁷Department of Medicine, University of Chicago, Chicago, IL, USA

Correspondence: Dr MV Relling, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794, USA. E-mail: mary.relling@stjude.org

Received 23 March 2007; Revised 27 June 2007; Accepted 28 June 2007; Published online 2 August 2007.

Abstract

The genetic risk factors for etoposide-induced leukemia with MLL translocations remain largely unknown. To identify genetic risk factors for and novel characteristics of secondary leukemia, we profiled 116 204 single nucleotide polymorphisms (SNPs) in germline and paired leukemic cell DNA from 13 secondary leukemia/myelodysplasia cases and germline DNA from 13 matched and 156 unmatched controls, all with acute lymphoblastic leukemia treated with etoposide. We analyzed global gene expression from a partially overlapping cohort. No single locus was altered in most cases. We discovered 81 regions of loss of heterozygosity (LOH) in leukemic blasts and 309 SNPs whose allele frequencies differed in cases vs controls. Candidate genes were prioritized on the basis of genes whose SNPs or expression differentiated cases from controls or showed LOH or copy number change in germline vs paired blast DNA from the13 cases. Three biological pathways were altered: adhesion, Wnt signaling and regulation of actin. Validation experiments using a genome scan for etoposide-induced leukemogenic MLL chimeric fusions in 15 HapMap cell lines also implicated genes involved in adhesion, a process linked to de novo leukemogenesis. Independent clinical epidemiologic and in vitro genome-wide approaches converged to identify novel pathways that may contribute to therapy-induced leukemia.