Deadly instability

A study led by Ludwig San Diego’s Don Cleveland and his former postdoc Ofer Shoshani along with Floris Foijer of the University of Groningen found that inducing random chromosome instability (CIN) events in mice for as little as one week suffices to trigger harmful chromosomal patterns in cells that spur the formation of tumors. Reported in Genes & Development in July, the findings confirm a nearly 120-year-old hypothesis, proposed by the German biologist Theodor Boveri, that aneuploidy—an abnormal number of chromosomes—drives tumorigenesis. The researchers transiently overexpressed the gene for polo-like kinase 4 (Plk4) in mice, inducing the production of cells in the animals with unequal numbers of chromosomes. Just one week of such overexpression induced aggressive T cell lymphomas often characterized by cells with triplicates of chromosomes 4, 5, 14 and 15. The team showed that the generation of aneuploidy is an early event in cancer initiation, and that transient CIN events can drive tumorigenesis regardless of whether p53—a major tumor suppressor that is frequently mutated in human cancer—is inactivated. The findings are of high relevance to people receiving aneugens, chemotherapies that cause chromosome instability and aneuploidy, suggesting that they might be at risk for secondary cancers induced by therapy.

This article appeared in the February 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).


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