Submitted June 28, 2007
Accepted January 13, 2008
Mutation of C/EBP
predisposes to the development of myeloid leukemia in a retroviral insertional mutagenesis screen
Marie Sigurd Hasemann, Inge Damgaard, Mikkel Bruhn Schuster, Kim Theilgaard-Monch, Annette Balle Sorensen, Alan Mrsic, Thijs Krugers, Bauke Ylstra, Finn Skou Pedersen, Claus Nerlov, and Bo Torben Porse*
Section for Gene Therapy Research, Copenhagen University Hospital, Copenhagen, Denmark
Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark
The Biotech Research and Innovation Centre, Copenhagen University Hospital, Copenhagen, Denmark
Department of Molecular Biology, University of Aarhus, Aarhus, Denmark
Department of Pathology, VU Medical Centre (VUMC), Amsterdam, Netherlands
EMBL Mouse Biology Unit, Monterotondo, Italy
* Corresponding author; email: porse{at}rh.dk.
C/EBP
is an important myeloid tumour suppressor that is frequently mutated in human Acute Myeloid Leukemia (AML). We have previously shown that mice homozygous for the E2F repression deficient CebpaBRM2 allele develop non-fatal AML with long latency and incomplete penetrance, suggesting that accumulation of secondary mutations is necessary for disease progression. Here we use SRS19-6-driven retroviral insertional mutagenesis to compare the phenotypes of leukemias arising in Cebpa+/+, Cebpa+/BRM2 and CebpaBRM2/BRM2 mice, with respect to disease type, latency of tumour development and identity of the retroviral insertion sites (RIS). Both Cebpa+/BRM2 and CebpaBRM2/BRM2 mice preferentially develop myeloid leukemias, but with differing latencies, thereby demonstrating the importance of gene dosage. Determination of RIS led to the identification of several novel candidate oncogenes, some of which may collaborate specifically with the E2F repression-deficient allele of Cebpa. Finally, we used an in silico pathway analysis approach to extract additional information from single RIS leading to the identifcation of signaling pathways which were preferentially deregulated in a disease- and/or genotype-specific manner.
