Foijer F, Xie SZ, Simon JE, Bakker PL, Conte N, Davis SH, Kregel E, Jonkers J, Bradley A, and Sorger PK (2014). Chromosome Instability Induced by Mps1 and P53 Mutation Generates Aggressive Lymphomas Exhibiting Aneuploidy-Induced Stress. Proc Natl Acad Sci U S A PMC4169945 PMID: 25197064.
Abstract
Aneuploidy is a hallmark of human solid cancers that arises from errors in mitosis and results in gain and loss of oncogenes and tumor suppressors. Aneuploidy poses a growth disadvantage for cells grown in vitro, suggesting that cancer cells adapt to this burden. To understand better the consequences of aneuploidy in a rapidly proliferating adult tissue, we engineered a mouse in which chromosome instability was selectively induced in T cells. A flanked by Lox mutation was introduced into the monopolar spindle 1 (Mps1) spindle-assembly checkpoint gene so that Cre-mediated recombination would create a truncated protein (Mps1DK) that retained the kinase domain but lacked the kinetochore-binding domain and thereby weakened the checkpoint. In a sensitized p53+/- background we observed that Mps1DK/DK mice suffered from rapid-onset acute lymphoblastic lymphoma. The tumors were highly aneuploid and exhibited a metabolic burden similar to that previously characterized in aneuploid yeast and cultured cells. The tumors nonetheless grew rapidly and were lethal within 3-4 mo after birth.