Transient genomic instability drives tumorigenesis through accelerated clonal evolution
Out now in Genes and Development (http://genesdev.cshlp.org/content/early/recent), a collaborative study from the Foijer lab at ERIBA and the Don Cleveland lab at the Ludwig Cancer Research Institute in San Diego, USA. This study describes how transient CIN induced by reversible Plk4 overexpression efficiently triggers acute T-ALL in p53+/- and p53-/- mic. These T-ALLs display the same karyotype landscape as T-ALLs that form in Mad2; p53 conditional knockouts displaying a chronic CIN phenotype. The karyotype landscape between the T-ALLs forming in both genotypes is remarkably similar and includes amplification of chromosomes 4, 5, 14 and 15. They find that all tumors overexpress c-Myc and display a transcriptome signature similar of human cancer. Single cell DNA sequencing reveals that the main difference between both models is that transient CIN is more efficient to maintain a tumor optimal karyotype. Future work should compare these T-ALL models for differences in becoming drug resistant. The study reveals that transient CIN is a powerful driver of tumorigenesis and published back-to-back with an elegant study from the late Angelika Amon lab that shows that c-Myc is the driver of chromosome 15 amplification in yet another model for CIN-induced lymphoma. Intriguingly, the karyotype landscape of these T-ALLs is near identical to the landscape observed in Cleveland/Foijer models, underlining how selection of particular karyotypes drives cancer. This research was co-funded by the Dutch Cancer Society.
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