Acute Myeloid Leukaemia
Our research started with studying the pathways and processes that underpin the initiation, progression and drug resistance of Acute Myeloid Leukaemia (AML). Early work looked at intra-cellular pro-survival responses to cytotoxic stress and identified pro-tumoral roles for HO-1, FLIP1, NRF-2 and BTK in AML proliferation. We extended our studies to identify cell surface SDF1/CXCR4, CD117 and FLT3-ITD as receptors which signal through BTK in AML cells. This work subsequently led to clinical trials of ibrutinib in AML patients. We were the first to report the anti-platelet effect of ibrutinib as the cause for the bleeding observed in the early phase clinical trials of patients with leukaemia and lymphoma.
More recently our focus has turned to the role of the bone marrow microenvironment and its fundamental role in supporting tumour growth. We found that hypoxia drives AML blasts to secrete macrophage migratory inhibitory factor (MIF) which in turn up-regulates pro-tumoral IL-6 and IL-8 release from the bone marrow stromal cells (BMSC) in the leukaemia microenvironment. In addition, we identified novel AML regulated changes in tumour metabolism. AML induces bone marrow adipocytes to breakdown triglyceride and release free fatty acid which then promotes leukaemia growth and AML blasts steal mitochondria from neighbouring BMSC to support ATP production via oxidative phosphorylation in the blast cells. In human AML we discovered that AML derived NOX2 generates superoxide, which in turn stimulates transfer of mitochondria from BMSC to AML blast through AML-derived tunnelling nanotubes. Furthermore, we have found that a prerequisite for BMSC to AML mitochondrial transfer is tumour driven up-regulation of mitochondrial biogenesis in the BMSC.