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, f33% 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.

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

“…High CUX1 expression was previously shown to inversely correlate with relapse-free and overall survival in high-grade breast cancers 36 . In transgenic mice, CUX1 was reported to cause various cancerassociated disorders depending on the specific isoform and tissue type expression 34,[43][44][45][46] . In particular, expression of CUX1 caused organomegaly in several organs including the liver 43 .…”

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

“…Transgenic mouse models have established that higher expression of several CUX1 isoforms increases cancer incidence 16,17,61 and that cytokinesis failure cooperates with the p75 and p110 CUX1 transcription factors in tumorigenicity 19 , whereas a Kras oncogene cooperates with the p200 CUX1 DNA repair accessory factor 18 . A hemizygous mouse knockout model should be used in the future to verify that inactivation of one Cux1 allele promotes tumorigenicity, particularly in the myeloid compartment, and to identify molecular events that cooperate with Cux1 hemizygosity in tumour development.…”

“…Consistent with this, transgenic mice expressing various CUX1 isoforms exhibit multiorgan hyperplasia 15 and develop myelo proliferative disease (MPD)-like myeloid leukaemias 16 and tumours in the mammary gland [17][18][19] , the lung 18 and the uterus 20 . Many cell lines with CUX1 LOH that are listed on the Sanger cancer cell line website (see Further information) harbour amplification of the remaining allele, illustrating the dual role of CUX1 in cancer (TABLE 1).…”

“…and sarcomas were observed in mice of the FVB genetic background, expression of MMTV-p75 CUX1 in mice of mixed genetic backgrounds (129/Ola x FVB or 129/Ola x C57BL/6) caused a disease defined as an MPD-like myeloid leukaemia and characterized by massive expansion of neutrophils in the blood, spleen, bone marrow and non-haematopoietic organs, such as the kidneys and the lungs 16 . In addition, expression of the p75 CUX1 isoform under the control of the cytomegalovirus immediate early enhancer and the chicken β-actin promoter caused polycystic kidneys at variable penetrance and severity, correlating with transgene expression levels 61 .…”

“…In addition, p200 CUX1 promotes genome stability through its role in base excision repair 18 . Such functions would not predict a role as an oncogene, but overexpression of either p200 or p110 CUX1 contributes to tumorigenicity in cell culture models 21,24 and in transgenic mice 16,17,19,20,61 (reviewed in REFS 28,67). Two studies showed that cancer cells are acutely dependent on the multiple roles of CUX1 in maintaining genome integrity 18,19 .…”