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Blood, 15 January 2008, Vol. 111, No. 2, pp. 790-799.
Prepublished online as a Blood First Edition Paper on September 28, 2007; DOI 10.1182/blood-2007-07-098236.
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Submitted July 5, 2007
Accepted September 19, 2007
Quantitative expression profiling guided by common retroviral insertion sites reveals novel and cell type-specific cancer genes in leukemia
Martin Sauvageau, Michelle Miller, Sebastien Lemieux, Julie Lessard, Josee Hebert, and Guy Sauvageau*
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), Montreal, Quebec, Canada
Functional and Structural Bioinformatics Laboratory, Institute for Research in Immunology and Cancer (IRIC), Montreal, Quebec, Canada
Leukemia Cell Bank of Quebec and Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
Department of Medicine, University of Montreal, Montreal, Quebec, Canada
* Corresponding author; email: guy.sauvageau{at}umontreal.ca.
Proviral insertional mutagenesis is a powerful tool for the discovery of cancer-associated genes. The ability of integrated proviruses to affect gene expression over long distances combined with the lack of methods to determine the expression levels of a large number of genes in a systematic and truly quantitative manner have limited the identification of cancer-associated genes by proviral insertional mutagenesis. Here we have characterized a new model of proviral insertional mutagenesis-induced lymphoid tumors derived from Eed polycomb group gene mutant mice and quantitatively determined the expression levels of all genes within 100kb of 20 different retroviral common insertion sites (CIS) identified in these tumors. Using a high-throughput quantitative RT-PCR approach, we document an average of 13 CIS-associated genes deregulated per tumor, half of which are leukemia subtype-specific, while the others are coordinately deregulated in the majority of tumors analyzed. Interestingly, we find that genes located distantly from common proviral integration sites are as frequently deregulated as proximal genes, with an average of  2 genes affected per integration. Our studies reveal an unsuspected conservation in the group of genes deregulated among phenotypically similar subtypes of lymphoid leukemias, and suggest that identification of common molecular determinants of this disease is within reach.
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