title: Chromosomal instability triggered by Rrm2b loss leads to IL-6 secretion and plasmacytic neoplasms.
abstract: 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.
authors: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. lchang@coh.org
authors: Lufen
authors: L
authors: Chang
authors: Robin
authors: R
authors: Guo
authors: Qin
authors: Q
authors: Huang
authors: Yun
authors: Y
authors: Yen
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D018932:Chemokine CCL2 / Q000378:metabolism; D043171:Chromosomal Instability; D004247:DNA / Q000378:metabolism; D005838:Genotype; D006579:Heterozygote; D051550:I-kappa B Kinase / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007621:Karyotyping; D007952:Leukemia, Plasma Cell / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D012264:Ribonucleotide Reductases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D051996:Transcription Factor RelA; D004247:DNA; D012264:Ribonucleotide Reductases; C486561:Rrm2b protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D051550:I-kappa B Kinase
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