Understanding the Biology of the Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) are a heterogenous group of clonal haematopoietic stem cell malignancies causing low blood counts with a propensity to transform to acute leukaemia. This blood cancer occurs primarily in the elderly, and the incidence of this disease will continue to increase with our ageing population. The only potentially curative therapy for MDS is an allogeneic haematopoietic stem cell transplant, which is not a feasible option in the majority of these elderly patients with other precluding medical comorbidities. The mainstay of treatment for the patients with lower risk disease, who make up almost 75% of MDS patients, is supportive management with blood transfusions which carry a risk of iron overload.
Consistent with a number of observational studies, our lab has also found haematopoietic improvement in patients with low risk disease treated for iron overload with the iron chelator Deferasirox (DFX).
We have preliminary data from our laboratory demonstrating that iron chelation blocked cell growth and proliferation of myeloid cell lines with mitochondrial dysfunction and apoptosis of malignant clones. We hypothesise that this iron chelator has a role in autophagy, a cellular recycling process that contributes to the pathogenesis of this disease.
We have looked at the effect of iron modulation on autophagy in myeloid cell lines. Utilising the CRISPR/Cas9 genome editing to knockout essential autophagy genes in various cell lines, we will be looking at the effect of this cellular process in the propagation of the malignant clone as well as erythroid differentiation, as MDS are characterised by ineffective erythropoiesis. We are also looking at iron modulation in a mouse model of MDS and its effect on halting progression of disease.
With increasing knowledge of immune dysfunction in MDS and its impact on transformation of disease from low risk to high risk, we are also looking at exploring immunomodulatory mechanisms as potential disease modifying agents.
Dr Chris Slape
A/Professor Paul Ekert
A/Professor Ron Firestein
Prof Stephen Opat