Whole chromosome loss and associated breakage–fusion–bridge cycles transform mouse tetraploid cells |
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| Authors: | Rozario Thomas Daniel Henry Marks Yvette Chin Robert Benezra |
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| Affiliation: | 1. BCMB Program, Weill Cornell Graduate School of Medical Sciences (WCGSMS), New York, NY, USA;2. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA |
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| Abstract: | Whole chromosome gains or losses (aneuploidy) are a hallmark of ~70% of human tumors. Modeling the consequences of aneuploidy has relied on perturbing spindle assembly checkpoint (SAC) components, but interpretations of these experiments are clouded by the multiple functions of these proteins. Here, we used a Cre recombinase‐mediated chromosome loss strategy to individually delete mouse chromosomes 9, 10, 12, or 14 in tetraploid immortalized murine embryonic fibroblasts. This methodology also involves the generation of a dicentric chromosome intermediate, which subsequently undergoes a series of breakage–fusion–bridge (BFB) cycles. While the aneuploid cells generally display a growth disadvantage in vitro, they grow significantly better in low adherence sphere‐forming conditions and three of the four lines are transformed in vivo, forming large and invasive tumors in immunocompromised mice. The aneuploid cells display increased chromosomal instability and DNA damage, a mutator phenotype associated with tumorigenesis in vivo. Thus, these studies demonstrate a causative role for whole chromosome loss and the associated BFB‐mediated instability in tumorigenesis and may shed light on the early consequences of aneuploidy in mammalian cells. |
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| Keywords: | aneuploidy chromosomal instability chromosome losses tetraploidy tumorigenesis |
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