title: Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress.
abstract: Aneuploidy is a hallmark of human solid cancers that arises from errors in mitosis and results in gain and loss of oncogenes and tumor suppressors. Aneuploidy poses a growth disadvantage for cells grown in vitro, suggesting that cancer cells adapt to this burden. To understand better the consequences of aneuploidy in a rapidly proliferating adult tissue, we engineered a mouse in which chromosome instability was selectively induced in T cells. A flanked by Lox mutation was introduced into the monopolar spindle 1 (Mps1) spindle-assembly checkpoint gene so that Cre-mediated recombination would create a truncated protein (Mps1(DK)) that retained the kinase domain but lacked the kinetochore-binding domain and thereby weakened the checkpoint. In a sensitized p53(+/-) background we observed that Mps1(DK/DK) mice suffered from rapid-onset acute lymphoblastic lymphoma. The tumors were highly aneuploid and exhibited a metabolic burden similar to that previously characterized in aneuploid yeast and cultured cells. The tumors nonetheless grew rapidly and were lethal within 3-4 mo after birth.
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, NL-9713 AV, Groningen, The Netherlands; Department of Systems Biology, Harvard Medical School, Boston, MA 02115; Mouse Genomics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom; and f.foijer@umcg.nl peter_sorger@hms.harvard.edu.
authors.forename: Floris
authors.initials: F
authors.lastname: Foijer
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Stephanie Z
authors.initials: SZ
authors.lastname: Xie
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, NL-9713 AV, Groningen, The Netherlands;
authors.forename: Judith E
authors.initials: JE
authors.lastname: Simon
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, NL-9713 AV, Groningen, The Netherlands;
authors.forename: Petra L
authors.initials: PL
authors.lastname: Bakker
authors.affiliation: Mouse Genomics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom; and.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Conte
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Davis
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, NL-1066 CX, Amsterdam, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Kregel
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, NL-1066 CX, Amsterdam, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Mouse Genomics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom; and.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; f.foijer@umcg.nl peter_sorger@hms.harvard.edu.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Sorger
mesh_terms: D000782:Aneuploidy; D000818:Animals; D043171:Chromosomal Instability / Q000235:genetics*; D002869:Chromosome Aberrations; D002999:Clone Cells; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic; D006579:Heterozygote; D006801:Humans; D007621:Karyotyping; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary; D013312:Stress, Physiological / Q000235:genetics*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; C441620:Ttk protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: CIN; T-cell acute lymphoblastic lymphoma; chromosomal instability; mouse models; tumor metabolism