Despite advances in understanding the pathogenesis of blood cancers such as acute myeloid leukaemia (AML) and multiple myeloma (MM), long-term survival rates for these types of cancers remain low.  Moreover, existing therapies for AML and MM are complex and toxic for both children and adults. Identifying the molecular processes which contribute to the onset of an anti-apoptotic phenotype will enable the development of targeted therapeutic interventions for AML and MM. Our group is focussed on the regulation of cell death by the transcription factor NF-κB, as it regulates the expression of a group of genes which play a central role in tumourogenesis, and which also define a cell's life/death balance.  These pathways are considered a major barrier to effective therapy of leukaemias and myelomas.  In normal healthy cells NF-κB is inactivated under basal conditions and is activated in response to a number of inflammatory stumuli. We have discovered in AML and MM, that NF-κB is constitutively activated, thus switching on genes that protect cells from undergoing apoptosis. This has led to the development of NF-κB inhibitors (eg Bortezomib) for the treatment of certain cancers including multiple myeloma. However, the effectiveness of such inhibitors in inducing apoptosis in leukaemic cells has been disappointing. We recently identified the cytoprotective antioxidant response element (ARE) signalling pathway and its transcriptional activator NRF2, to be highly active also in AML and MM, and explains why NF-κB inhibitors have limited success of chemotherapy in these patients. We showed that NF-κB-inhibited cells super-induce expression of a range of cytoprotective genes, which protects AML and MM cell from cytotoxic cell death. This pathway represents a novel target to be able to effectively treat many drug-resistant forms of blood cancers. This research project aims to determine the role of cytoprotective antioxidant genes in types of human leukaemias and myelomas.  We will assess the effectiveness of clinically used and new chemotherapy cytotoxic agents on primary samples from leukaemia and myeloma patients in order to determine the role of these pathways in protecting chemotherapy-resistant forms of such blood cancers.

Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L and MacEwan DJ (2012) "BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB" Cell Signalling (EPub).

Heasman S-A, Zaitseva L, Bowles KM, Rushworth SA and MacEwan DJ (2011) "Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1" Oncotarget 2, 658-668.

Rushworth SA, Bowles KM and MacEwan DJ (2011) "High basal nuclear Nrf2 in human AML reduces sensitivity towards proteasome inhibitors" Cancer Res 71, 1999-2009.

Rushworth SA and MacEwan DJ (2008) "HO-1 underlies resistance of AML cells to TNF-induced apoptosis" Blood 111, 3793-3801.

Rae C, Langa S, Tucker SJ and MacEwan DJ (2007) "Elevated NF-κB responses and FLIP levels in leukemic, but not normal lymphocytes: reduction by salicylate allows TNF-induced apoptosis" Proc Natl Acad Sci USA 104, 12790–12795.