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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4309-4321.
Prepublished online as a Blood First Edition Paper on January 22, 2008; DOI 10.1182/blood-2007-06-097790.
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NEOPLASIA
Mutation of C/EBP predisposes to the development of myeloid leukemia in a retroviral insertional mutagenesis screen
Marie S. Hasemann13,
Inge Damgaard13,
Mikkel B. Schuster13,
Kim Theilgaard-Mönch13,
Annette B. Sørensen4,
Alan Mr i 5,
Thijs Krugers5,
Bauke Ylstra5,
Finn S. Pedersen4,
Claus Nerlov6, and
Bo T. Porse13
1 Section for Gene Therapy Research and
2 Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark;
3 The Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark;
4 Department of Molecular Biology, University of Aarhus, Aarhus, Denmark;
5 Department of Pathology, VU Medical Centre (VUMC), Amsterdam, The Netherlands; and
6 European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo, Italy
The CCAAT enhancer binding protein  (C/EBP) is an important myeloid tumor 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 nonfatal 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 tumor development, and identity of the retroviral insertion sites (RISs). Both Cebpa+/BRM2 and CebpaBRM2/BRM2 mice preferentially develop myeloid leukemias, but with differing latencies, thereby demonstrating the importance of gene dosage. Determination of RISs 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 RISs, leading to the identification of signaling pathways which were preferentially deregulated in a disease- and/or genotype-specific manner.
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