Lefebure, MarcusTothill, Richard WKruse, ElizabethHawkins, Edwin DShortt, JakeMatthews, Geoffrey MGregory, Gareth PMartin, Benjamin PKelly, Madison JTodorovski, IzabelaDoyle, Maria ALupat, RichardLi, JasonSchroeder, JanWall, MeaghanCraig, StuartPoortinga, GretchenCameron, DonBywater, MeganKats, LevGearhart, Micah DBardwell, Vivian JDickins, Ross AHannan, Ross DPapenfuss, Anthony TJohnstone, Ricky W2017-05-092017-05-092041-1723http://hdl.handle.net/1885/116828The Eμ-Myc mouse is an extensively used model of MYC driven malignancy; however to date there has only been partial characterization of MYC co-operative mutations leading to spontaneous lymphomagenesis. Here we sequence spontaneously arising Eμ-Myc lymphomas to define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive mutations in the PRC1-like component and BCL6-corepressor gene Bcor. Moreover, we find unexpected concomitant multigenic lesions involving Cdkn2a loss and other cancer genes including Nras, Kras and Bcor. These findings challenge the assumed two-hit model of Eμ-Myc lymphoma and demonstrate a functional in vivo role for Bcor in suppressing tumorigenesis.We acknowledge the following funding agencies: Leukaemia Foundation of Australia, Arrow Bone Marrow Transplant Foundation, National Health and Medical Research Council Australia, Cancer Council Victoria, Victorian Cancer Agency, Australian Cancer Research Foundation, Peter MacCallum Cancer Centre Foundation, National Institutes of Health.10 pagesapplication/pdf© The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Eμ-MycmouseMYCmalignancylymphomatransgenearchitecturesomaticmutationstructuralalterationcancergenesNrasKrasBcor2017-03-0610.1038/ncomms14581