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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