Mutation of C/EBP{alpha} predisposes to the development of myeloid leukemia in a retroviral insertional mutagenesis screen

C/EBPalpha 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 Cebpa(BRM2) 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 Cebpa(BRM2/BRM2) mice, with respect to disease type, latency of tumour development and identity of the retroviral insertion sites (RIS). Both Cebpa(+/BRM2) and Cebpa(BRM2/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.
Udgivelsesdato: 2008-Jan-22