Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma

Abstract

Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases. The resulting DNA copy number variation and patterns of chromosome loss and gain are tumor-type specific, suggesting differential selective pressures on the two tumor cell types.DOI: http://dx.doi.org/10.7554/eLife.20873.001

CIN and Aneuploidy: Different Concepts, Different Consequences

“…However, MEFs become much more tolerant of CIN when p53 was also deleted, [23] although long term cultures of SAC-deficient MEFs are difficult to maintain. [72] Similar to what is observed in vitro, high-grade CIN is not tolerated when provoked early in development: for instance full SAC abrogation through Mad2 inactivation in the mouse, with or without p53 deletion, yields early embryonic death. [23,73] However, high-grade CIN is not always lethal in vivo.…”

“…[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).…”

“…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.…”

“…[80][81][82][83][84][85][86][87][88][89] The karyotypes observed in cancer are not random, as different cancer types display specific karyotypes. [36,72,90] While certain forms of aneuploidy can be beneficial to tumor growth, the relationship between cancer and CIN remains paradoxical. On the one hand CIN itself can lead to tumorigenesis in some models, [91,92] but on the other hand, CIN has been found to act as a tumor suppressor in other models.…”

Degree and site of chromosomal instability define its oncogenic potential

“…Mouse models of CIN have occasionally shown sporadic, spontaneous tumors with very long latency (>12-18 months), and predominantly in spleen and lung [21][22][23][24][25][26][27][28][29] , suggesting CIN is not a potent cancer driver. In mice predisposed to cancer, CIN is either neutral [30][31][32] , promotes tumor formation 23,26,27,30,[33][34][35][36][37][38][39] , or, in some conditions, suppresses it 29,30,32,37 .…”