Positive and negative regulation of lymphomagenesis by the NF-kappaB subunit c-Rel

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, counter-intuitively, 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). Q-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 ChIP-Seq data revealed that Bach2 is a c-Rel and NF-κB target gene in transformed human B-cells, while treatment of Burkitt''s lymphoma cells with inhibitors of the NF-κB/IKK pathway or deletion of c-Rel or RelA resulted in loss of Bach2 expression. This data reveals 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.'

ORGANISM(S): Mus musculus

SUBMITTER: Simon Cockell 

PROVIDER: E-MTAB-2774 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress