Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 37, Pages 13427-13432Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1400892111
Keywords
chromosomal instability; mouse models; CIN; tumor metabolism; T-cell acute lymphoblastic lymphoma
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Funding
- Dutch Cancer Society [RUG 2012-5549]
- Stichting Kinder Oncologie Groningen
- European Molecular Biology Organization
- National Institutes of Health (NIH) [CA084179, CA139980]
- NIH [P30-CA14051]
- Wellcome Trust
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Aneuploidy is a hallmark of human solid cancers that arises from errors in mitosis and results in gain and loss of oncogenes and tumor suppressors. Aneuploidy poses a growth disadvantage for cells grown in vitro, suggesting that cancer cells adapt to this burden. To understand better the consequences of aneuploidy in a rapidly proliferating adult tissue, we engineered a mouse in which chromosome instability was selectively induced in T cells. A flanked by Lox mutation was introduced into the monopolar spindle 1 ( Mps1) spindle-assembly checkpoint gene so that Cre- mediated recombination would create a truncated protein ( Mps1(DK)) that retained the kinase domain but lacked the kinetochore-binding domain and therebyweakened the checkpoint. In a sensitized p53(+/-) background we observed that Mps1(DK/DK) mice suffered from rapid-onset acute lymphoblastic lymphoma. The tumors were highly aneuploid and exhibited a metabolic burden similar to that previously characterized in aneuploid yeast and cultured cells. The tumors nonetheless grew rapidly and were lethal within 3-4 mo after birth.
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