TY - JOUR
T1 - Chromosomal Instability Triggered by Rrm2b Loss Leads to IL-6 Secretion and Plasmacytic Neoplasms
AU - Chang, Lufen
AU - Guo, Robin
AU - Huang, Qin
AU - Yen, Yun
N1 - Funding Information:
We thank Michael Karin (UCSD) for helpful comments on the manuscript, Yibin Wang (UCLA) for adenoviruses expressing IκBα mutant super-repressor (S32A, S36A), Yusuke Nakamura (University of Tokyo) for Rrm2b −/− fibroblasts, and Yafan Wang for searching MM specimens in the TLR Core. This research was supported by grants from the Lymphoma SPORE to L.C. and Y.Y., the Tim Nesvig Lymphoma Research Foundation to L.C. and Y.Y., and the National Cancer Institute (5R01CA127541) to Y.Y.
PY - 2013/5/30
Y1 - 2013/5/30
N2 - Chronic inflammation has a tight cause-and-effect relationship with DNA damage by inflicting tissue damage and increasing cancer risk. Rrm2b, a key enzyme in de novo deoxyribonucleotide synthesis, is involved in DNA damage repair, but its role in cancer development has yet to be demonstrated. In this work, Rrm2b gene loss led to severe numerical and structural chromosome abnormalities that caused ATM activation, inducing p-Ser85 IKKγ/NEMO and IκB kinase (IKK). NF-κB consequently induced by IKK triggered sustained IL-6 expression that constitutively activated STAT3 in Rrm2b-deficient cells. High plasma interleukin-6 (IL-6) and associated hematologic disorders were observed in Rrm2b-/- mice, and 30%-40% of aged Rrm2b heterozygous knockout mice developed plasma cell neoplasms and suffered from progressive splenomegaly and ascites. The genetic ablation of IL-6 suppressed STAT3 induction and delayed disease onset in Rrm2b-/- mice, extending their lifespan. Thus, Rrm2b plays a crucial role in maintaining chromosomal stability and preventing chronic-inflammation-associated tumorigenesis.
AB - Chronic inflammation has a tight cause-and-effect relationship with DNA damage by inflicting tissue damage and increasing cancer risk. Rrm2b, a key enzyme in de novo deoxyribonucleotide synthesis, is involved in DNA damage repair, but its role in cancer development has yet to be demonstrated. In this work, Rrm2b gene loss led to severe numerical and structural chromosome abnormalities that caused ATM activation, inducing p-Ser85 IKKγ/NEMO and IκB kinase (IKK). NF-κB consequently induced by IKK triggered sustained IL-6 expression that constitutively activated STAT3 in Rrm2b-deficient cells. High plasma interleukin-6 (IL-6) and associated hematologic disorders were observed in Rrm2b-/- mice, and 30%-40% of aged Rrm2b heterozygous knockout mice developed plasma cell neoplasms and suffered from progressive splenomegaly and ascites. The genetic ablation of IL-6 suppressed STAT3 induction and delayed disease onset in Rrm2b-/- mice, extending their lifespan. Thus, Rrm2b plays a crucial role in maintaining chromosomal stability and preventing chronic-inflammation-associated tumorigenesis.
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U2 - 10.1016/j.celrep.2013.03.040
DO - 10.1016/j.celrep.2013.03.040
M3 - Article
C2 - 23643536
AN - SCOPUS:84878597409
SN - 2211-1247
VL - 3
SP - 1389
EP - 1397
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -
