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Oncogene. 2015 May 21;34(21):2807-13. doi: 10.1038/onc.2014.211. Epub 2014 Jul 21.

Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor.

Author information

1
Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
2
Section of General Surgery, Department of Surgery, The University of Chicago, Chicago, IL, USA.
3
Institute for Genomics and Systems Biology, Department of Pathology, The University of Chicago, Chicago, IL, USA.
4
Institute for Genomics and Systems Biology, Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
5
Department of Pediatrics, The University of Chicago, Chicago, IL, USA.
6
Department of Radiation and Cellular Oncology, and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA.

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.

PMID:
25043302
PMCID:
PMC4302074
DOI:
10.1038/onc.2014.211
[Indexed for MEDLINE]
Free PMC Article

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