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Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor

Oncogene volume 34, pages 2807–2813 (2015)Cite this article

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Abstract

NF-κB proteins play a central and subunit-specific role in the response to DNA damage. Previous work identified p50/NF-κB1 as being necessary for cytotoxicity in response to DNA alkylation damage. Given the importance of damage-induced cell death for the maintenance of genomic stability, we examined whether Nfkb1 acts as a tumor suppressor in the setting of alkylation damage. Hprt mutation analysis demonstrates that Nfkb1−/− cells accumulate more alkylator-induced, but not ionizing radiation (IR)-induced, mutations than similarly treated wild-type cells. Subsequent in vivo tumor induction studies reveal that following alkylator treatment, but not IR, Nfkb1−/− mice develop more lymphomas than similarly treated Nfkb1+/+ animals. Heterozygous mice develop lymphomas at an intermediate rate and retain functional p50 in their tumors, indicating that Nfkb1 acts in a haploinsufficient manner. Analysis of human cancers, including therapy-related myeloid neoplasms, demonstrates that NFKB1 mRNA expression is downregulated compared with control samples in multiple hematological malignancies. These data indicate that Nfkb1 is a haploinsufficient, pathway-specific tumor suppressor that prevents the development of hematologic malignancy in the setting of alkylation damage.

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Acknowledgements

We are grateful to RF de Pooter and B Kee for helpful contributions. This work was supported by NIH grant 1R01CA136937 (to BY), The Ludwig Center for Metastasis Research; Leukemia & Lymphoma Society Fellow award (M.E.M) and the Chicago Cancer Genomes Project.

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Author notes

  1. D J Voce, A M Schmitt and A Uppal: These authors contributed equally to this work.

Authors and Affiliations

  1. Section of Neurosurgery, The University of Chicago, Chicago, IL, USA

    D J Voce, A M Schmitt, G M Bernal, K E Cahill, J S Wahlstrom, A Nassiri, X Yu, C D Crawley & B Yamini

  2. Department of Surgery, Section of General Surgery, The University of Chicago, Chicago, IL, USA

    A Uppal

  3. Department of Pathology, Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA

    M E McNerney

  4. Department of Human Genetics, Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA

    K P White

  5. Department of Pediatrics, The University of Chicago, Chicago, IL, USA

    K Onel

  6. Department of Radiation and Cellular Oncology, and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA

    R R Weichselbaum

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  1. D J Voce
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Correspondence to B Yamini.

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Voce, D., Schmitt, A., Uppal, A. et al. Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor. Oncogene 34, 2807–2813 (2015). https://doi.org/10.1038/onc.2014.211

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  • DOI: https://doi.org/10.1038/onc.2014.211

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