Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress

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 (Mps1 DK ) that retained the kinase domain but lacked the kinetochore-binding domain and thereby weakened the checkpoint. In a sensitized p53 +/− background we observed that Mps1 DK/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.

Too much to handle — how gaining chromosomes destabilizes the genome

“…49 Remarkably, aneuploidy induced by Mps1 truncation can lead to oncogenic transformation only in combination with heterozygous p53 deletion triggering upregulation of cell cycle related pahtways. 50 Not surprisingly, MCM2, MCM3 and MCM7 have been found up-regulated in some type of tumors. [51][52][53] Thus, in future it will be important to analyze the role of p53 in the gene deregulation during the response of human cells to chronic aneuploidy.…”

CIN and Aneuploidy: Different Concepts, Different Consequences

“…[75,93,94] Furthermore, yet other CIN models are suggesting that CIN only enhances tumorigenesis in a tumorprone background. [16,32,72,95,96] These inconsistent findings may be explained by different rates and types of CIN in the various models. Indeed, it has been suggested that high rates of CIN inhibit tumor progression, while lower CIN rates allow for tumor evolution [5,93,94] (also see Figure 2b and c).…”

“…The effects of CIN have been found to be strongly dependent on the rate and type of chromosome mis-segregation or mitotic defect. [14][15][16][17][18] CIN is often measured in a tissue culture setting, which we, for the purpose of this review, define as in vitro. CIN can be quantified via time-lapse microscopy or immunofluorescence staining of fixed cells in mitosis.…”

“…[14][15][16][17][18] In vitro CIN measurements can also be used to characterize animal models. For instance, some studies make use of mouse embryonic fibroblasts (MEFs) from mouse models of genetically induced CIN to estimate the in vivo rate of CIN.…”

“…This indicates that aneuploid cells, while not cancerous initially, are prone to adopt a malignant fate when combined with other predisposing mutations. [16,36,72] Interestingly, a recent study suggests that aneuploid cells might be cleared by the immune system. In this study CIN is induced to create senescent, aneuploid cells that were then cocultured with natural killer cells (NK92) in vitro.…”