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

Jessica Woodward, Gillian C. Taylor, Dinesh C. Soares, Shelagh Boyle, Daoud Sie, David Read, Keerthi Chathoth, Milica Vukovic, Nuria Tarrats, David Jamieson, Kirsteen J Campbell, Karen Blyth, Juan Carlos Acosta, Bauke Ylstra, Mark J. Arends, Kamil R. Kranc, Andrew P. Jackson, Wendy A. Bickmore, Andrew J. Wood

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)2173-2186
Number of pages14
JournalGenes and Development
Issue number19
Early online date13 Oct 2016
Publication statusPublished - 2016

Keywords / Materials (for Non-textual outputs)

  • chromosome structure
  • condensin
  • genome instability
  • lymphoma
  • mitosis


Dive into the research topics of 'Condensin II mutation causes T cell lymphoma through tissue-specific genome instability'. Together they form a unique fingerprint.

Cite this