| First Author | Voce DJ | Year | 2015 |
| Journal | Oncogene | Volume | 34 |
| Issue | 21 | Pages | 2807-13 |
| PubMed ID | 25043302 | Mgi Jnum | J:222538 |
| Mgi Id | MGI:5644795 | Doi | 10.1038/onc.2014.211 |
| Citation | Voce DJ, et al. (2015) Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor. Oncogene 34(21):2807-13 |
| abstractText | NF-kappaB proteins play a central and subunit-specific role in the response to DNA damage. Previous work identified p50/NF-kappaB1 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. |
