Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability

Woodward, J. et al. (2016) Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability. Genes and Development, 30(19), pp. 2173-2186. (doi: 10.1101/gad.284562.116) (PMID:27737961)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Blyth, Professor Karen and Campbell, Dr Kirsteen
• Authors: Woodward, J., Taylor, G. C., Soares, D. C., Boyle, S., Sie, D., Read, D., Chathoth, K., Vukovic, M., Tarrats, N., Jamieson, D., Campbell, K., Blyth, K., Acosta, J. C., Ylstra, B., Arends, M. J., Kranc, K. R., Jackson, A. P., Bickmore, W. A., and Wood, A. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Genes and Development
• Publisher: Cold Spring Harbor Laboratory Press
• ISSN: 0890-9369
• ISSN (Online): 1549-5477
• Published Online: 13 October 2016
• Copyright Holders: Copyright © 2016 Woodward et al.
• First Published: First published in Genes and Development 30(19):2173-2186
• Publisher Policy: Reproduced under a Creative Commons License