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

Floris Foijer,Allan Bradley,Roderick T Bronson,Lee A Albacker,Stephanie Z Xie,Bjorn Bakker,Darin Takemoto,Annegret Lutum-Jehle,Brinley Furey,Peter M Lansdorp,Stephanie Davis,Peter K Sorger,Diana C Spierings,Ying Yue,Brian Hare

doi:10.7554/elife.20873

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.

Highlights

Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is a hallmark of solid tumors and in human cancers is frequently an indicator of poor prognosis
We have previously shown that deletion of Mad2l1 (HUGO MD2L1; UniProt Q9Z1B5), an essential component of the spindle assembly checkpoint (SAC), is tolerated by murine interfollicular epidermal cells, which terminally differentiate to form the outer layers of the skin, but not by hair follicle bulge stem cells, a specialized self-renewing cell type required for hair follicle maintenance (Foijer et al, 2013)
In this paper we describe an analysis of tumorigenesis in mice carrying a conditional Mad2l1 deletion in a highly proliferative cell type (T-cells) and in a second cell type in which proliferation is induced by injury

Summary

Introduction

Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is a hallmark of solid tumors and in human cancers is frequently an indicator of poor prognosis. The same is true of cells from Down syndrome patients, which carry a supernumerary chromosome 21 (Williams et al, 2008; Jones et al, 2010) It remains poorly understood how the oncogenic effects of genomic instability as a driver of gene gain and loss, and the burden of aneuploidy in reducing fitness play out in real tumors. It has been suggested that tumors experience a burst of chromosome instability (CIN) leading to the emergence of clones with greater oncogenic potential but that CIN is suppressed so that cancer cells maintain a relatively stable karyotype (Lengauer et al, 1997; Wang et al, 2014).

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