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Chromosome Instability Induced by Mps1 and P53 Mutation Generates Aggressive Lymphomas Exhibiting Aneuploidy-Induced Stress

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Chromosome Instability Induced by Mps1 and P53 Mutation Generates Aggressive Lymphomas Exhibiting Aneuploidy-Induced Stress Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress Floris Foijera,b,c,1,2, Stephanie Z. Xieb,1,3, Judith E. Simona, Petra L. Bakkera, Nathalie Contec, Stephanie H. Davisb, Eva Kregeld, Jos Jonkersd, Allan Bradleyc, and Peter K. Sorgerb,2 aEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, NL-9713 AV, Groningen, The Netherlands; bDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115; cMouse Genomics, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom; and dDivision of Molecular Pathology, The Netherlands Cancer Institute, NL-1066 CX, Amsterdam, The Netherlands Edited by Don W. Cleveland, University of California, San Diego, La Jolla, CA, and approved August 5, 2014 (received for review January 17, 2014) Aneuploidy is a hallmark of human solid cancers that arises from predisposing and tumor suppressing, depending on the context errors in mitosis and results in gain and loss of oncogenes and tumor (18). Hypomorphic BubR1 mutations also have the unexpected suppressors. Aneuploidy poses a growth disadvantage for cells property of promoting progeria (11). grown in vitro, suggesting that cancer cells adapt to this burden. Conditional mutations typically yield tumor phenotypes more To understand better the consequences of aneuploidy in a rapidly representative of human disease than germ-line mutations (19), proliferating adult tissue, we engineered a mouse in which chromo- but conditional alleles have been little studied in the case of the some instability was selectively induced in T cells. A flanked by spindle checkpoint. We therefore engineered a conditional flanked Lox mutation was introduced into the monopolar spindle 1 (Mps1) by Lox (FLOX) mutation into Mps1, a gene thought to function spindle-assembly checkpoint gene so that Cre-mediated recombina- DK upstream in the SAC pathway (20) and then selectively truncated tion would create a truncated protein (Mps1 ) that retained the the protein by expressing Cre recombinase in T cells. The Mps1 kinase domain but lacked the kinetochore-binding domain and Mps1DK +/− truncation (deletion in the kinetochore domain; ) GENETICS thereby weakened the checkpoint. In a sensitized p53 background we observed that Mps1DK/DK mice suffered from rapid-onset acute removes the kinase-targeting domain but leaves the rest of the lymphoblastic lymphoma. The tumors were highly aneuploid and protein intact. We show that expression of this truncated protein exhibited a metabolic burden similar to that previously character- causes chromosomal instability in MEFs and aneuploidy in two Mps1 ized in aneuploid yeast and cultured cells. The tumors nonetheless different Cre-expressing mouse lines. truncation in combina- p53 grew rapidly and were lethal within 3–4 mo after birth. tion with heterozygous deletion leads to early-onset lympho- blastic lymphoma and consequent death. In lymphoma cells, chromosomal instability | mouse models | CIN | tumor metabolism | changes in the expression of metabolic, splicing, and DNA-synthesis T-cell acute lymphoblastic lymphoma Significance neuploidy is a hallmark of oncogenesis, affecting two out of Athree cancers (1). Aneuploidy arises during mitosis as a re- Normal cells rarely missegregate chromosomes, but the majority sult of chromosomal instability (CIN) (2–4). The frequent oc- of cancer cells have a chromosomal instability (CIN) phenotype currence of CIN in solid human tumors suggests a fundamental that makes errors more common and results in abnormal chro- link between aneuploidy and cancer (5). However, primary mouse mosomal content (aneuploidy). Although aneuploidy promotes embryonic fibroblasts (MEFs) carrying a supernumerary chro- transformation via gain of oncogenes and loss of tumor sup- mosome have decreased proliferative potential, as do cells isolated pressors, it also slows cell proliferation and disrupts metabolic from Down syndrome patients (6, 7) implying that chromosome homeostasis. Aneuploidy therefore represents a liability as well imbalance imposes a physiological burden that lowers fitness, at as a source of selective advantage for cancer cells. We provoked least in untransformed cells (6, 8–10). In some mouse models, CIN CIN in murine T cells by weakening the spindle-assembly check- appears to have a significant impact on lifespan at the organismal point and then studied the consequences. We found that CIN level, with increased aneuploidy decreasing life expectancy and dramatically accelerates cancer in a genetically predisposed vice versa (11–13). However, how the fitness cost imposed by CIN background and that the resulting aneuploid cancers are meta- is balanced by its potential to promote oncogenic transformation bolically deranged, a vulnerability that may open new avenues remains poorly understood. to treating aneuploid cancers. Mouse models of CIN involving conditional or hypomorphic mutations in spindle-assembly checkpoint (SAC) genes provide Author contributions: F.F., S.Z.X., and P.K.S. designed research; F.F., S.Z.X., J.E.S., P.L.B., S.H.D., and E.K. performed research; N.C. and A.B. contributed new reagents/analytic a means to study aneuploidy and assess its impact on cell fitness tools; F.F., S.Z.X., J.E.S., N.C., J.J., A.B., and P.K.S. analyzed data; and F.F. and P.K.S. wrote and oncogenesis. The SAC detects the presence of maloriented or the paper. detached kinetochores during mitosis and arrests cells in meta- The authors declare no conflict of interest. phase until all pairs of sister chromatids achieve the bioriented This article is a PNAS Direct Submission. geometry that is uniquely compatible with normal disjunction Freely available online through the PNAS open access option. (14–16). The SAC constitutes a signaling cascade [comprising Data deposition: The data reported in this paper have been deposited in the Gene Ex- monopolar spindle 1 (Mps1), Bub, Mad, CenpE, and RZZ pro- pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE57334). teins] that blocks activation of the anaphase-promoting complex, 1F.F. and S.Z.X. contributed equally to this work. and thus mitotic progression, until all chromosomes are properly 2To whom correspondence may be addressed. Email: [email protected] or peter_sorger@ aligned (17). In the mouse, germ-line deletion of SAC genes hms.harvard.edu. results in early embryonic lethality, whereas heterozygous 3Present address: Princess Margaret and Toronto General Hospitals, University Health knockout of Mad2 and other SAC genes generates relatively weak Network, Toronto, Canada M5G 2C1. – tumor phenotypes late in life (2 4). Paradoxically, some SAC This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. mutations (e.g., CenpE heterozygosity) appear to be both tumor 1073/pnas.1400892111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1400892111 PNAS Early Edition | 1of6 genes are very similar to changes previously identified in aneu- panels), Fig. S1 D and E,andMovies S1 and S2]. We conclude DK ploid yeast and cultured murine cells (6, 8) and appear to con- that the Mps1 mutation impairs but does not prevent kineto- stitute a hallmark of chromosomal imbalance. chore binding, a conclusion supported by overexpression studies in human MCF 10A cells (Fig. S1 F and G and Movies S3 and S4). Results DK To provoke CIN in a tissue-restricted fashion, we engineered The Mps1 Truncation Weakens the SAC and Causes CIN. To de- f a conditional Mps1 truncation allele by flanking exons 3 and 4 of termine the consequences of Mps1 mutation for chromosome Mps1f/f the Mps1 locus with lox-sites; correct targeting of Mps1 in mouse segregation at a cellular level, we isolated embryos, gener- ated MEFs, and transduced them with retroviruses expressing ES cells was confirmed by Southern blotting and RT-PCR (Fig. doxycycline (Dox)-inducible Cre (GFP-T2A-Cre). We found that S1 A–C and SI Materials and Methods). Upon expression of Cre f exposure of these cells to Dox resulted in highly efficient switching, Mps1 DK recombinase (21), the allele generates a truncated Mps1 yielding Mps1 MEFs within 24–48 h (Fig. 1C, compare lanes – kinase lacking residues 47 154,adomaininvolvedinkinetochore 1 and 2 with lane 4). Some recombination also was observed in the binding (Fig. 1A) (22). When expressed in MEFs as a GFP fusion, absence of Dox (Fig. 1C, lane 3). When treated with the spindle f/f DK the Mps1DK protein had the anticipated molecular weight but, poison nocodazole, both control Mps1 and Mps1 MEFs arres- unlike wild-type Mps1-GFP, did not accumulate to the same levels ted in mitosis, showing that both cell types can respond to spindle B disassembly (Fig. 1D). However, when time-lapse imaging was used on prometaphase kinetochores [Fig. 1 (compare upper and lower DK/DK to assay the duration of arrest, Mps1 cells were observed to exit mitosis 150 ± 16 min after DNA condensation, in contrast to f/f 264 ± 15 min in control cells (congenic Mps1 cells not exposed Kinetochore- Kinase Mps1WT-GFP Mps1WT-GFP P < E A binding domain domain B to Cre), a significant difference ( 0.0001) (Fig. 1 ). The ob- Mps1DK 1830200 520 servation that cells expressing are unable to sustain mitotic arrest in the presence of spindle damage suggests that the SAC DK 50 aa is impaired but not inactivated by the Mps1 mutation (23) and Deleted in Mps1DK confirms our goal in creating the allele. C Mps1DK 6:00 12:00 f Time-lapse imaging in the absence of nocodazole showed that Mps1 DK DK DK CreDox-ind - - + + Mps1 -GFP Mps1 -GFP H2B-Cherry–transduced Mps1 MEFs spent ∼40% longer in Dox - + - + mitosis than control cells (Fig. 1F and Fig. S1H). In addition, they F G ) frequently contained lagging chromosomes (Fig. 1 and and 10 D pos Movies S5, S6,andS7; control cells are shown in Movies S8 and 8 S9), and half of all the cells failed to form a proper metaphase plate 6:00 12:00 (Movie 10), resulting in polyploidy (Fig.
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