Transient genomic instability drives tumorigenesis through accelerated clonal evolution
| Autor: | Benjamin Vitre, Diana C.J. Spierings, Dong Hyun Kim, Bjorn Bakker, Lauren de Haan, Kathleen M. Fisch, René Wardenaar, Floris Foijer, Jon Artates, Andréa E. Tijhuis, Marcus Maldonado, Yin Wang, Ouyang Zhengyu, Don W. Cleveland, Matthew A. Demarest, Ofer Shoshani, Adam Mark, Roman Sasik |
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| Přispěvatelé: | Ludwig Institute for Cancer Research, 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: | 2021 |
| Předmět: |
Genome instability
p53 CENTROSOME AMPLIFICATION Aneuploidy [SDV.CAN]Life Sciences [q-bio]/Cancer Tumor initiation Myc Biology medicine.disease_cause Somatic evolution in cancer Genomic Instability Clonal Evolution Mice 03 medical and health sciences 0302 clinical medicine LYMPHOMAS Chromosomal Instability Chromosome instability Genetics medicine Animals cancer PROMOTE 030304 developmental biology Centrosome 0303 health sciences ANEUPLOIDY medicine.disease 3. Good health Spindle checkpoint Cell Transformation Neoplastic 030220 oncology & carcinogenesis Plk4 Cancer research Carcinogenesis Trisomy chromosome instability Research Paper Developmental Biology |
| Zdroj: | Genes Dev Genes & Development, 35(15-16), 1093-1108. COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT |
| ISSN: | 0890-9369 |
| Popis: | Abnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we generated mice with random aneuploidies by transient induction of polo-like kinase 4 (Plk4), a master regulator of centrosome number. Short-term chromosome instability (CIN) from transient Plk4 induction resulted in formation of aggressive T-cell lymphomas in mice with heterozygous inactivation of one p53 allele and accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphoma-initiating cells with a specific karyotype profile, including trisomy of chromosomes 4, 5, 14, and 15 occurring early in tumorigenesis. Tumor development in mice with chronic CIN induced by an independent mechanism (through inactivation of the spindle assembly checkpoint) gradually trended toward a similar karyotypic profile, as determined by single-cell whole-genome DNA sequencing. Overall, we show how transient CIN generates cells with random aneuploidies from which ones that acquire a karyotype with specific chromosome gains are sufficient to drive cancer formation, and that distinct CIN mechanisms can lead to similar karyotypic cancer-causing outcomes. |
| Databáze: | OpenAIRE |
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