Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation / genetics
  • Animals
  • Cell Death / genetics
  • DNA Damage / genetics*
  • Down-Regulation / genetics
  • Female
  • Haploinsufficiency / genetics*
  • Heterozygote
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B p50 Subunit / genetics*
  • RNA, Messenger / genetics
  • Radiation, Ionizing
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics*


  • NF-kappa B p50 Subunit
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Nfkb1 protein, mouse