title: Transgenic mice expressing the p75 CCAAT-displacement protein/Cut homeobox isoform develop a myeloproliferative disease-like myeloid leukemia.
abstract: The p75 CCAAT-displacement protein/Cut homeobox (CDP/Cux) isoform was previously reported to be overexpressed in human breast cancers. To investigate its oncogenic potential, we engineered two transgenic mouse lines expressing p75 CDP/Cux under the control of the mouse mammary tumor virus-long terminal repeat. The FVB strain of mouse is generally used in the generation of mouse models for breast cancer. The transgene was introduced into the hprt locus of 129/Ola embryonic stem cells and, following germ line passage, was backcrossed onto the FVB and C57BL/6 mouse strains. Here, we describe the phenotype of p75 CDP/Cux transgenic virgin female mice of the first backcross generations. We report that after a long latency period, approximately 33% of mice from two independent transgenic lines and from backcrosses into either the FVB or the C57BL/6 strains succumbed to a similar disease characterized by splenomegaly, hepatomegaly, and frequent infiltration of leukocytes into nonhematopoietic organs like the kidneys and lungs. Although an excess of B or T cells was observed in three diseased mice, in 17 other cases, histologic and flow cytometry analyses revealed the expansion of a population of neutrophils in the blood, spleen, and bone marrow. The increase in neutrophils correlated with signs of anemia and thrombocytopenia, whereas there was no indication of a reactive process. Therefore, p75 CDP/Cux transgenic mice displayed heightened susceptibility to a disease defined as a myeloproliferative disease-like myeloid leukemia. These results indicate that the overexpression of p75 CDP/Cux could alter homeostasis in the hematopoietic compartment.
authors.affiliation: Molecular Oncology Group, McGill University Health Center, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Cadieux
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournier
authors.forename: Alan C
authors.initials: AC
authors.lastname: Peterson
authors.forename: Christian
authors.initials: C
authors.lastname: Bédard
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Bedell
authors.forename: Alain
authors.initials: A
authors.lastname: Nepveu
mesh_terms: D000818:Animals; D002460:Cell Line; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D006410:Hematopoiesis / Q000502:physiology; D006529:Hepatomegaly / Q000235:genetics / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D013163:Splenomegaly / Q000235:genetics / Q000473:pathology; D020079:Terminal Repeat Sequences / Q000235:genetics; D014157:Transcription Factors
chemical_list: C080632:CUX1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors