1. Cancer Biology
  2. Chromosomes and Gene Expression
Download icon

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

  1. Floris Foijer  Is a corresponding author
  2. Lee A Albacker
  3. Bjorn Bakker
  4. Diana C Spierings
  5. Ying Yue
  6. Stephanie Z Xie
  7. Stephanie H Davis
  8. Annegret Lutum-Jehle
  9. Darin Takemoto
  10. Brian Hare
  11. Brinley Furey
  12. Roderick T Bronson
  13. Peter M Lansdorp
  14. Allan Bradley
  15. Peter K Sorger  Is a corresponding author
  1. University Medical Center Groningen, Netherlands
  2. Harvard Medical School, United States
  3. University Health Network, Canada
  4. Vertex Pharmaceuticals Incorporated, United States
  5. BC Cancer Agency, Canada
  6. Wellcome Trust Sanger Institute, United Kingdom
Research Article
  • Cited 20
  • Views 1,487
  • Annotations
Cite this article as: eLife 2017;6:e20873 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.

Article and author information

Author details

  1. Floris Foijer

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    For correspondence
    f.foijer@umcg.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0989-3127
  2. Lee A Albacker

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bjorn Bakker

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Diana C Spierings

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Ying Yue

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephanie Z Xie

    Princess Margaret and Toronto General Hospitals, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephanie H Davis

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0022-4210
  8. Annegret Lutum-Jehle

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Darin Takemoto

    Vertex Pharmaceuticals Incorporated, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Brian Hare

    Vertex Pharmaceuticals Incorporated, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Brinley Furey

    Vertex Pharmaceuticals Incorporated, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Roderick T Bronson

    Rodent Histopathology Core Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Peter M Lansdorp

    Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Allan Bradley

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Peter K Sorger

    Department of Systems Biology, Harvard Medical School, Boston, United States
    For correspondence
    peter_sorger@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institute for Health Research (CA084179)

  • Lee A Albacker
  • Ying Yue
  • Stephanie H Davis
  • Peter K Sorger

National Institute for Health Research (CA139980)

  • Lee A Albacker
  • Ying Yue
  • Stephanie H Davis
  • Peter K Sorger

KWF Kankerbestrijding (2012-RUG-5549)

  • Floris Foijer
  • Bjorn Bakker

H2020 European Research Council (ERC advanced ROOTS)

  • Diana C Spierings
  • Peter M Lansdorp

European Molecular Biology Organization (Longterm fellowship)

  • Floris Foijer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animals were kept in pathogen-free housing under guidelines approved by the Center for Animal Resources and Comparative Medicine at Harvard Medical School or at the Wellcome Trust Sanger Institute. Animal protocols were approved by the Massachusetts Institute of Technology, Harvard Medical School Committees on Animal Care (IACUC numbers I04272 and IS00000178), UK Home Office, and UMCG animal facility (DEC 6369).

Reviewing Editor

  1. Angelika Amon, Howard Hughes Medical Institute, Massachusetts Institute of Technology, United States

Publication history

  1. Received: August 23, 2016
  2. Accepted: March 18, 2017
  3. Accepted Manuscript published: March 20, 2017 (version 1)
  4. Version of Record published: April 21, 2017 (version 2)

Copyright

© 2017, Foijer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,487
    Page views
  • 363
    Downloads
  • 20
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Chromosomes and Gene Expression
    Xiao Ling Li et al.
    Research Article Updated

    Long noncoding RNAs (lncRNAs) are often associated with polysomes, indicating coding potential. However, only a handful of endogenous proteins encoded by putative lncRNAs have been identified and assigned a function. Here, we report the discovery of a putative gastrointestinal-tract-specific lncRNA (LINC00675) that is regulated by the pioneer transcription factor FOXA1 and encodes a conserved small protein of 79 amino acids which we termed FORCP (FOXA1-Regulated Conserved Small Protein). FORCP transcript is undetectable in most cell types but is abundant in well-differentiated colorectal cancer (CRC) cells where it functions to inhibit proliferation, clonogenicity, and tumorigenesis. The epitope-tagged and endogenous FORCP protein predominantly localizes to the endoplasmic reticulum (ER). In response to ER stress, FORCP depletion results in decreased apoptosis. Our findings on the initial characterization of FORCP demonstrate that FORCP is a novel, conserved small protein encoded by a mis-annotated lncRNA that regulates apoptosis and tumorigenicity in well-differentiated CRC cells.

    1. Cancer Biology
    Hang Ruan et al.
    Research Article Updated

    To better understand a role of eIF4E S209 in oncogenic translation, we generated EIF4ES209A/+ heterozygous knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had little impact on total eIF4E levels, cap binding or global translation, but markedly reduced HCT 116 cell growth in spheroids and mice, and CRC organoid growth. 4EKI strongly inhibited Myc and ATF4 translation, the integrated stress response (ISR)-dependent glutamine metabolic signature, AKT activation and proliferation in vivo. 4EKI inhibited polyposis in ApcMin/+ mice by suppressing Myc protein and AKT activation. Furthermore, p-eIF4E was highly elevated in CRC precursor lesions in mouse and human. p-eIF4E cooperated with mutant KRAS to promote Myc and ISR-dependent glutamine addiction in various CRC cell lines, characterized by increased cell death, transcriptomic heterogeneity and immune suppression upon deprivation. These findings demonstrate a critical role of eIF4E S209-dependent translation in Myc and stress-driven oncogenesis and as a potential therapeutic vulnerability.