Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma
| Autor: | Lee A. Albacker, Roderick T. Bronson, Darin Takemoto, Diana C.J. Spierings, Floris Foijer, Brian Hare, Ying Yue, Peter K. Sorger, Stephanie Z. Xie, Stephanie H. Davis, Bjorn Bakker, Peter M. Lansdorp, Brinley Furey, Allan Bradley, Annegret Lutum-Jehle |
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| Přispěvatelé: | Foijer, Floris [0000-0003-0989-3127], Davis, Stephanie [0000-0002-0022-4210], Apollo - University of Cambridge Repository, Stem Cell Aging Leukemia and Lymphoma (SALL), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Mad2 T-Lymphocytes Aneuploidy CHROMOSOME INSTABILITY Mice MITOTIC CHECKPOINT MAMMALIAN-CELLS Chromosome instability P53-DEFICIENT MICE karyotype heterogeneity Biology (General) genes IN-VIVO cancer biology Sequence Deletion Chromothripsis General Neuroscience Karyotype General Medicine 3. Good health Spindle checkpoint Genes and Chromosomes P53 GENE Mad2 Proteins Medicine STEM-CELLS Research Article chromosomes Carcinoma Hepatocellular chromosomal instability Cell Survival QH301-705.5 Science Biology Lymphoma T-Cell General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cancer stem cell medicine Animals PROMOTES TUMORIGENESIS BREAST-CANCER human aneuploidy mouse General Immunology and Microbiology medicine.disease Molecular biology Disease Models Animal 030104 developmental biology Cancer cell Hepatocytes M Phase Cell Cycle Checkpoints spindle checkpoint |
| Zdroj: | eLife, Vol 6 (2017) eLife eLife, 6:20873. ELIFE SCIENCES PUBLICATIONS LTD |
| ISSN: | 2050-084X |
| Popis: | 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. DOI: http://dx.doi.org/10.7554/eLife.20873.001 eLife digest An estimated 350 billion of the cells in the human body are dividing at any given moment. Every cell division requires the 46 chromosomes in the cell, which store the genetic information that the cell needs to survive, to be copied and distributed evenly between the two new cells. Sometimes mistakes in cell division can result in cells that have the wrong number of chromosomes – a state called aneuploidy. Aneuploidy is rare in healthy cells but occurs in over 75% of cancers. It is the result of a process called chromosomal instability that often leads to the death of healthy cells. However, it is not well understood how aneuploidy affects how cancer cells develop or behave. Mice are commonly used to investigate cancer because they have many genetic similarities with humans. To better understand the relationship between aneuploidy and cancer, Foijer, Albacker et al. engineered mice in which they could induce aneuploidy in liver cells and immune cells called T-cells. This modification accelerated the formation of liver cancer and lymphoma – a cancer of the immune system. The number of chromosomes in the cells of these cancers varied greatly, demonstrating that these cells experience constant chromosomal instability. Overall, this suggests that aneuploidy increases the likelihood of cancer developing. The mouse cancer cells closely resemble their human counterparts, and so could potentially be used to test new cancer drugs. In the future, developing new therapies that selectively target aneuploid cells could result in cancer treatments that have fewer side effects than existing treatments. DOI: http://dx.doi.org/10.7554/eLife.20873.002 |
| Databáze: | OpenAIRE |
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