title: Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability.
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.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Woodward
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Gillian C
authors.initials: GC
authors.lastname: Taylor
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.|Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Dinesh C
authors.initials: DC
authors.lastname: Soares
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Shelagh
authors.initials: S
authors.lastname: Boyle
authors.affiliation: Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.
authors.forename: Daoud
authors.initials: D
authors.lastname: Sie
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Read
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Keerthi
authors.initials: K
authors.lastname: Chathoth
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.
authors.forename: Milica
authors.initials: M
authors.lastname: Vukovic
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Nuria
authors.initials: N
authors.lastname: Tarrats
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4AD, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Jamieson
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom.
authors.forename: Kirsteen J
authors.initials: KJ
authors.lastname: Campbell
authors.affiliation: Cancer Research UK Beatson Institute, Bearsden, Glasgow G61 1BD, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Acosta
authors.affiliation: Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.affiliation: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arends
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom.|Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Kamil R
authors.initials: KR
authors.lastname: Kranc
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Bickmore
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Andrew J
authors.identifier: http://orcid.org/0000-0002-0653-2070
authors.initials: AJ
authors.lastname: Wood
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000705:Anaphase; D000818:Animals; D002478:Cells, Cultured; D022004:Chromosome Structures / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D042822:Genomic Instability / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008677:Metaphase; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D060168:Thymocytes / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics* / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C108312:condensin complexes; D000251:Adenosine Triphosphatases
keywords: chromosome structure; condensin; genome instability; lymphoma; mitosis