%0 Journal Article %1 Hunter2016 %A Hunter, J. E. %A Butterworth, J. A. %A Zhao, B. %A Sellier, H. %A Campbell, K. J. %A Thomas, H. D. %A Bacon, C. M. %A Cockell, S. J. %A Gewurz, B. E. %A Perkins, N. D. %D 2016 %I Macmillan Publishers Limited %J Oncogene %K myown %N 26 %P 3476-3484 %T The NF-kappaB subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma %U http://dx.doi.org/10.1038/onc.2015.399 %V 35 %X The REL gene, encoding the NF-kappaB 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, Emu-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 Emu-Myc lymphoma cells but, counterintuitively, c-rel-/- Emu-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-/- Emu-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 Emu-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 Emu-Myc mice. Analysis of wild-type Emu-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-kappaB target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-kappaB/IkappaB 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-kappaB signalling in cancer.

@article{Hunter2016, abstract = {The REL gene, encoding the NF-[kappa]B 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, E[mu]-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 E[mu]-Myc lymphoma cells but, counterintuitively, c-rel-/- E[mu]-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-/- E[mu]-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 E[mu]-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 E[mu]-Myc mice. Analysis of wild-type E[mu]-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-[kappa]B target gene in transformed human B cells, whereas treatment of Burkitt's lymphoma cells with inhibitors of the NF-[kappa]B/I[kappa]B 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-[kappa]B signalling in cancer.}, added-at = {2016-11-19T00:31:09.000+0100}, author = {Hunter, J. E. and Butterworth, J. A. and Zhao, B. and Sellier, H. and Campbell, K. J. and Thomas, H. D. and Bacon, C. M. and Cockell, S. J. and Gewurz, B. E. and Perkins, N. D.}, biburl = {https://www.bibsonomy.org/bibtex/2af59564ac8d19eaa65b33bff2b6aa7b0/bgewurz}, day = 30, interhash = {74cf2790b1cea04a80741703eac60f15}, intrahash = {af59564ac8d19eaa65b33bff2b6aa7b0}, issn = {0950-9232}, journal = {Oncogene}, keywords = {myown}, month = jun, note = {Short Communication}, number = 26, pages = {3476-3484}, publisher = {Macmillan Publishers Limited}, timestamp = {2016-11-19T01:47:04.000+0100}, title = {The NF-[kappa]B subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma}, url = {http://dx.doi.org/10.1038/onc.2015.399}, volume = 35, year = 2016 }