Mutation of C/EBPalpha predisposes to the development of myeloid leukemia in a retroviral insertional mutagenesis screen.

TY - JOUR

T1 - Mutation of C/EBPalpha predisposes to the development of myeloid leukemia in a retroviral insertional mutagenesis screen.

AU - Hasemann, Marie S

AU - Damgaard, Inge

AU - Schuster, Mikkel B

AU - Theilgaard-Mönch, Kim

AU - Sørensen, Annette B

AU - Mrsic, Alan

AU - Krugers, Thijs

AU - Ylstra, Bauke

AU - Pedersen, Finn Skou

AU - Nerlov, Claus

AU - Porse, Bo T

N1 - Keywords: Alleles; Animals; CCAAT-Enhancer-Binding Protein-alpha; Clone Cells; Computational Biology; Gene Expression Regulation, Leukemic; Gene Rearrangement; Genes, Neoplasm; Genetic Predisposition to Disease; Genomic Instability; Immunoglobulins; Injections; Leukemia, Myeloid; Mice; Mice, Inbred C57BL; Mutagenesis, Insertional; Mutation; Phenotype; Precancerous Conditions; Receptors, Antigen, T-Cell, alpha-beta; Retroviridae; Virus Latency

PY - 2008

Y1 - 2008

N2 - The CCAAT enhancer binding protein alpha (C/EBPalpha) 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 Cebpa(BRM2) 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 Cebpa(BRM2/BRM2) mice, with respect to disease type, latency of tumor development, and identity of the retroviral insertion sites (RISs). 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 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.

AB - The CCAAT enhancer binding protein alpha (C/EBPalpha) 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 Cebpa(BRM2) 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 Cebpa(BRM2/BRM2) mice, with respect to disease type, latency of tumor development, and identity of the retroviral insertion sites (RISs). 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 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.

U2 - 10.1182/blood-2007-06-097790

DO - 10.1182/blood-2007-06-097790

M3 - Journal article

C2 - 18212247

SN - 0006-4971

VL - 111

SP - 4309

EP - 4321

JO - Blood

JF - Blood

IS - 8

ER -