Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability
- Jessica Woodward1,
- Gillian C. Taylor1,
- Dinesh C. Soares1,2,
- Shelagh Boyle1,
- Daoud Sie3,
- David Read1,
- Keerthi Chathoth1,
- Milica Vukovic4,
- Nuria Tarrats5,
- David Jamieson6,
- Kirsteen J. Campbell7,
- Karen Blyth7,
- Juan Carlos Acosta5,
- Bauke Ylstra3,
- Mark J. Arends5,
- Kamil R. Kranc4,5,
- Andrew P. Jackson1,
- Wendy A. Bickmore1 and
- Andrew J. Wood1
- 1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;
- 2Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;
- 3Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands;
- 4MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom;
- 5Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;
- 6Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4AD, United Kingdom;
- 7Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom
- Corresponding authors: andrew.wood{at}igmm.ed.ac.uk, wendy.bickmore{at}igmm.ed.ac.uk
Abstract
Chromosomal instability is a hallmark of cancer, but mitotic regulators are rarely mutated in tumors. Mutations in the condensin complexes, which restructure chromosomes to facilitate segregation during mitosis, are significantly enriched in cancer genomes, but experimental evidence implicating condensin dysfunction in tumorigenesis is lacking. We report that mice inheriting missense mutations in a condensin II subunit (Caph2nes) develop T-cell lymphoma. Before tumors develop, we found that the same Caph2 mutation impairs ploidy maintenance to a different extent in different hematopoietic cell types, with ploidy most severely perturbed at the CD4+CD8+ T-cell stage from which tumors initiate. Premalignant CD4+CD8+ T cells show persistent catenations during chromosome segregation, triggering DNA damage in diploid daughter cells and elevated ploidy. Genome sequencing revealed that Caph2 single-mutant tumors are near diploid but carry deletions spanning tumor suppressor genes, whereas P53 inactivation allowed Caph2 mutant cells with whole-chromosome gains and structural rearrangements to form highly aggressive disease. Together, our data challenge the view that mitotic chromosome formation is an invariant process during development and provide evidence that defective mitotic chromosome structure can promote tumorigenesis.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.284562.116.
- Received May 23, 2016.
- Accepted September 15, 2016.
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