title: The NF-κB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma.
abstract: The REL gene, encoding the NF-κB subunit c-Rel, is frequently amplified in B-cell lymphoma and functions as a tumour-promoting transcription factor. Here we report the surprising result that c-rel-/- mice display significantly earlier lymphomagenesis in the c-Myc driven, Eμ-Myc model of B-cell lymphoma. c-Rel loss also led to earlier onset of disease in a separate TCL1-Tg-driven lymphoma model. Tumour reimplantation experiments indicated that this is an effect intrinsic to the Eμ-Myc lymphoma cells but, counterintuitively, c-rel-/- Eμ-Myc lymphoma cells were more sensitive to apoptotic stimuli. To learn more about why loss of c-Rel led to earlier onset of disease, microarray gene expression analysis was performed on B cells from 4-week-old, wild-type and c-rel-/- Eμ-Myc mice. Extensive changes in gene expression were not seen at this age, but among those transcripts significantly downregulated by the loss of c-Rel was the B-cell tumour suppressor BTB and CNC homology 2 (Bach2). Quantitative PCR and western blot analysis confirmed loss of Bach2 in c-Rel mutant Eμ-Myc tumours at both 4 weeks and the terminal stages of disease. Moreover, Bach2 expression was also downregulated in c-rel-/- TCL1-Tg mice and RelA Thr505Ala mutant Eμ-Myc mice. Analysis of wild-type Eμ-Myc mice demonstrated that the population expressing low levels of Bach2 exhibited the earlier onset of lymphoma seen in c-rel-/- mice. Confirming the relevance of these findings to human disease, analysis of chromatin immunoprecipitation sequencing data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-κB/IκB kinase pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. These data reveal a surprising tumour suppressor role for c-Rel in lymphoma development explained by regulation of Bach2 expression, underlining the context-dependent complexity of NF-κB signalling in cancer.
authors.affiliation: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University Medical School, Newcastle Upon Tyne, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Hunter
authors.affiliation: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University Medical School, Newcastle Upon Tyne, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Butterworth
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University Medical School, Newcastle Upon Tyne, UK.
authors.forename: H
authors.initials: H
authors.lastname: Sellier
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Campbell
authors.affiliation: Northern Institute for Cancer Research, Newcastle Upon Tyne, UK.
authors.forename: H D
authors.initials: HD
authors.lastname: Thomas
authors.affiliation: Northern Institute for Cancer Research, Newcastle Upon Tyne, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Bacon
authors.affiliation: Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Cockell
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: B E
authors.initials: BE
authors.lastname: Gewurz
authors.affiliation: Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University Medical School, Newcastle Upon Tyne, UK.
authors.forename: N D
authors.initials: ND
authors.lastname: Perkins
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D020569:Proto-Oncogene Proteins c-rel; C498144:Rela protein, mouse; C490393:Tcl1 protein, mouse; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins