Deletion of theMAD2L1spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma.
Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types.
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Systems Biology, Harvard Medical School, Boston, United States.
Floris
0000-0003-0989-3127
F
Foijer
Department of Systems Biology, Harvard Medical School, Boston, United States.
Lee A
LA
Albacker
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Bjorn
B
Bakker
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Diana C
DC
Spierings
Department of Systems Biology, Harvard Medical School, Boston, United States.
Ying
Y
Yue
Department of Systems Biology, Harvard Medical School, Boston, United States.
Stephanie Z
SZ
Xie
Department of Systems Biology, Harvard Medical School, Boston, United States.
Stephanie
0000-0002-0022-4210
S
Davis
Department of Systems Biology, Harvard Medical School, Boston, United States.
Annegret
A
Lutum-Jehle
Vertex Pharmaceuticals Incorporated, Cambridge, United States.
Darin
D
Takemoto
Vertex Pharmaceuticals Incorporated, Cambridge, United States.
Brian
B
Hare
Vertex Pharmaceuticals Incorporated, Cambridge, United States.
Brinley
B
Furey
Rodent Histopathology Core, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, United States.
Roderick T
RT
Bronson
Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada.
Peter M
PM
Lansdorp
Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Allan
A
Bradley
Department of Systems Biology, Harvard Medical School, Boston, United States.
Peter K
PK
Sorger
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002470:Cell Survival; D043171:Chromosomal Instability; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000502:physiology; D016399:Lymphoma, T-Cell / Q000473:pathology*; D059566:M Phase Cell Cycle Checkpoints; D064246:Mad2 Proteins / Q000235:genetics*; D051379:Mice; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000502:physiology
D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse
Mad2; aneuploidy; cancer biology; chromosomal instability; chromosomes; genes; human; karyotype heterogeneity; mouse; spindle checkpoint