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

Lookup NU author(s): Dr David Jamieson

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


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.


Publication metadata

Author(s): Woodward J, Taylor GC, Soares DC, Boyle S, Sie D, Read D, Chathoth K, Vukovic M, Tarrats N, Jamieson D, Campbell KJ, Blyth K, Acosta JC, Ylstra B, Arends MJ, Kranc KR, Jackson AP, Bickmore WA, Wood AJ

Publication type: Article

Publication status: Published

Journal: Genes & Development

Year: 2016

Volume: 30

Pages: 2173-2186

Online publication date: 13/10/2016

Acceptance date: 15/09/2016

Date deposited: 01/12/2016

ISSN (print): 0890-9369

ISSN (electronic): 1549-5477

Publisher: Cold Spring Harbour Laboratory Press

URL: http://dx.doi.org/10.1101/gad.284562.116

DOI: 10.1101/gad.284562.116


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