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Transgenic Mice Expressing the p75 CCAAT-Displacement Protein/Cut Homeobox Isoform Develop a Myeloproliferative Disease–Like Myeloid Leukemia

¹ Molecular Oncology Group, McGill University Health Center, Departments of ² Biochemistry, ³ Oncology, ⁴ Medicine, ⁵ Microbiology and Immunology, ⁶ Human Genetics, and ⁷ Pathology, McGill University; ⁸ McConnell Brain Imaging Centre, Montreal Neurological Institute; and Departments of ⁹ Pathology and ¹⁰ Microbiology, Faculty of Veterinary Medicine, Université de Montréal, Montreal, Quebec, Canada

Requests for reprints: Alain Nepveu, Molecular Oncology Group, McGill University, 687 Pine Avenue West, Room H5.21, Montreal, Quebec, Canada H3A 1A1. Phone: 514-934-1934 ext. 35842; Fax: 514-843-1478; E-mail: alain.nepveu{at}mcgill.ca.

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, 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. (Cancer Res 2006; 66(19): 9492-501)

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