Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma
- University Medical Center Groningen, Netherlands
- Harvard Medical School, United States
- University Health Network, Canada
- Vertex Pharmaceuticals Incorporated, United States
- BC Cancer Agency, Canada
- Wellcome Trust Sanger Institute, United Kingdom
Abstract
Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types.
Data availability
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Copy number changes (average and single cell) and matching transcriptomes of HCCs and T-ALLs isolated from Mad2 p53 conditional double knockout micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63689).
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Cytogenetic aberrations in Hepatocellular adenoma and carcinomaPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63100).
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Hepatocellular adenoma/carcinoma from Mad2 deficient hepatocytesPublicly available at the NCBI Sequence Read Archive (accession no: SRA191233).
Article and author information
Author details
Funding
National Institute for Health Research (CA084179)
- Lee A Albacker
- Ying Yue
- Stephanie H Davis
- Peter K Sorger
National Institute for Health Research (CA139980)
- Lee A Albacker
- Ying Yue
- Stephanie H Davis
- Peter K Sorger
KWF Kankerbestrijding (2012-RUG-5549)
- Floris Foijer
- Bjorn Bakker
H2020 European Research Council (ERC advanced ROOTS)
- Diana C Spierings
- Peter M Lansdorp
European Molecular Biology Organization (Longterm fellowship)
- Floris Foijer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animals were kept in pathogen-free housing under guidelines approved by the Center for Animal Resources and Comparative Medicine at Harvard Medical School or at the Wellcome Trust Sanger Institute. Animal protocols were approved by the Massachusetts Institute of Technology, Harvard Medical School Committees on Animal Care (IACUC numbers I04272 and IS00000178), UK Home Office, and UMCG animal facility (DEC 6369).
Copyright
© 2017, Foijer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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