1. Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor
- Author
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Xiaohong Yu, Abhineet Uppal, Ralph R. Weichselbaum, Megan E. McNerney, Bakhtiar Yamini, Ashley M. Nassiri, Giovanna M. Bernal, Joshua S. Wahlstrom, Kirk E. Cahill, Adam M. Schmitt, Kenan Onel, David J. Voce, Clayton D. Crawley, and Kevin P. White
- Subjects
Male ,Cancer Research ,Programmed cell death ,Heterozygote ,Myeloid ,Alkylation ,DNA damage ,Down-Regulation ,lymphoma ,Haploinsufficiency ,Biology ,Article ,NF-κB ,law.invention ,Mice ,Downregulation and upregulation ,law ,Radiation, Ionizing ,Genetics ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Cell Death ,Tumor Suppressor Proteins ,NF-kappa B p50 Subunit ,Heterozygote advantage ,Mice, Inbred C57BL ,DNA Alkylation ,medicine.anatomical_structure ,Hypoxanthine-guanine phosphoribosyltransferase ,Immunology ,Cancer research ,Suppressor ,Female ,tumor suppression - 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.
- Published
- 2014