title: Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor.
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.
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Voce
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Schmitt
authors.affiliation: Section of General Surgery, Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Uppal
authors.affiliation: Institute for Genomics and Systems Biology, Department of Pathology, The University of Chicago, Chicago, IL, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: McNerney
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Bernal
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Cahill
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Wahlstrom
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nassiri
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Crawley
authors.affiliation: Institute for Genomics and Systems Biology, Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: White
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, IL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Onel
authors.affiliation: Department of Radiation and Cellular Oncology, and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Section of Neurosurgery, The University of Chicago, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Yamini
mesh_terms: D000478:Alkylation / Q000235:genetics; D000818:Animals; D016923:Cell Death / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C073701:Nfkb1 protein, mouse