Genomic characterisation of Eμ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene

Marcus Lefebure; Richard W Tothill; Elizabeth Kruse; Edwin D Hawkins; Jake Shortt; Geoffrey M Matthews; Gareth P Gregory; Benjamin P Martin; Madison J Kelly; Izabela Todorovski; Maria A Doyle; Richard Lupat; Jason Li; Jan Schroeder; Meaghan Wall; Stuart Craig; Gretchen Poortinga; Don Cameron; Megan Bywater; Lev Kats; Micah D Gearhart; Vivian J Bardwell; Ross A Dickins; Ross D Hannan; Anthony T Papenfuss; Ricky W Johnstone

doi:10.1038/ncomms14581

Genomic characterisation of Eμ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene

Nat Commun. 2017 Mar 6:8:14581. doi: 10.1038/ncomms14581.

Authors

Marcus Lefebure^{1

2}, Richard W Tothill^{1

2

3}, Elizabeth Kruse¹, Edwin D Hawkins⁴, Jake Shortt^{1

5}, Geoffrey M Matthews⁶, Gareth P Gregory¹, Benjamin P Martin¹, Madison J Kelly¹, Izabela Todorovski¹, Maria A Doyle¹, Richard Lupat¹, Jason Li¹, Jan Schroeder⁴, Meaghan Wall^{7

8}, Stuart Craig¹, Gretchen Poortinga¹, Don Cameron¹, Megan Bywater¹, Lev Kats^{1

2}, Micah D Gearhart⁹, Vivian J Bardwell⁹, Ross A Dickins¹⁰, Ross D Hannan^{1

11}, Anthony T Papenfuss^{1

2

4}, Ricky W Johnstone^{1

2}

Affiliations

¹ The Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
² The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
³ Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia.
⁴ The Walter Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
⁵ School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing &Health Sciences, Clayton, Victoria 3168, Australia.
⁶ Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
⁷ Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
⁸ Department of Medicine, St Vincent's Hospital, University of Melbourne, Parkville, Victoria 3052, Australia.
⁹ Developmental Biology Center, Masonic Cancer Center, and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA.
¹⁰ Australian Centre for Blood Diseases, Monash University, AMREP Building, Commercial Road, The Alfred Hospital, Melbourne, Victoria 3004, Australia.
¹¹ Cancer Biology and Therapeutics Department, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 0200, Australia.

Abstract

The 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
B-Lymphocytes / immunology
B-Lymphocytes / metabolism*
B-Lymphocytes / pathology
CRISPR-Cas Systems
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / immunology
Disease Models, Animal
Gene Editing
Gene Expression Regulation, Neoplastic*
Gene Frequency
Janus Kinase 2 / genetics
Janus Kinase 2 / immunology
Lymphoma, B-Cell / genetics*
Lymphoma, B-Cell / immunology
Lymphoma, B-Cell / pathology
Mice
Mice, Transgenic
Mutation*
Proto-Oncogene Proteins c-myc / genetics*
Proto-Oncogene Proteins c-myc / immunology
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / immunology
Repressor Proteins / genetics*
Repressor Proteins / immunology
STAT5 Transcription Factor / genetics
STAT5 Transcription Factor / immunology
Transcriptome
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / immunology
Whole Genome Sequencing

Substances

Bcor protein, mouse
Cdkn2a protein, mouse
Cyclin-Dependent Kinase Inhibitor p16
Myc protein, mouse
Proto-Oncogene Proteins c-myc
Repressor Proteins
STAT5 Transcription Factor
Trp53 protein, mouse
Tumor Suppressor Protein p53
Jak2 protein, mouse
Janus Kinase 2
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)

Grants and funding

R01 CA071540/CA/NCI NIH HHS/United States