title: NF-κB and AKT signaling prevent DNA damage in transformed pre-B cells by suppressing RAG1/2 expression and activity.
abstract: In developing lymphocytes, expression and activity of the recombination activation gene protein 1 (RAG1) and RAG2 endonuclease complex is tightly regulated to ensure ordered recombination of the immunoglobulin genes and to avoid genomic instability. Aberrant RAG activity has been implicated in the generation of secondary genetic events in human B-cell acute lymphoblastic leukemias (B-ALLs), illustrating the oncogenic potential of the RAG complex. Several layers of regulation prevent collateral genomic DNA damage by restricting RAG activity to the G1 phase of the cell cycle. In this study, we show a novel pathway that suppresses RAG expression in cycling-transformed mouse pre-B cells and human pre-B B-ALL cells that involves the negative regulation of FOXO1 by nuclear factor κB (NF-κB). Inhibition of NF-κB in cycling pre-B cells resulted in upregulation of RAG expression and recombination activity, which provoked RAG-dependent DNA damage. In agreement, we observe a negative correlation between NF-κB activity and the expression of RAG1, RAG2, and TdT in B-ALL patients. Our data suggest that targeting NF-κB in B-ALL increases the risk of RAG-dependent genomic instability.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Katarina
authors.initials: K
authors.lastname: Ochodnicka-Mackovicova
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mahnoush
authors.initials: M
authors.lastname: Bahjat
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Timon A
authors.initials: TA
authors.lastname: Bloedjes
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Chiel
authors.initials: C
authors.lastname: Maas
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: de Bruin
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bende
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carel J M
authors.initials: CJ
authors.lastname: van Noesel
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jeroen E J
authors.identifier: http://orcid.org/0000-0001-6894-3441
authors.initials: JE
authors.lastname: Guikema
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression; D016654:Genes, RAG-1; D016313:Genes, abl; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014170:Transformation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018398:Homeodomain Proteins; D007145:Immunoglobulin kappa-Chains; D016328:NF-kappa B; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064658:RAG-1 protein; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt