The myelodysplastic syndromes (MDS) are a group of clonal haematopoietic stem cell diseases characterised by cytopenia(s), dysplasia in one or more myeloid cell lineages, ineffective haematopoiesis and an increased risk of developing acute myeloid leukaemia. In low-to-intermediate risk MDS the bone marrow is composed of a mixture of defective and normal haematopoietic stem and progenitor cells. It has been postulated that the presence of cytokines such as TNFα and IFNγ in the bone marrow environment of MDS patients is pro-inflammatory that in turn suppresses haematopoiesis from normal stem cells whilst promoting the survival of abnormal clones culminating in the evolution of the disease. MDS patients exhibit a varying degree and number of cytopenias that often require blood transfusions. Some studies have suggested an adverse impact of transfusion dependence and iron overload on survival in low-to-intermediate risk MDS necessitating iron chelation therapy (ICT). A recently published meta-analysis of 8 observational studies strongly supports the notion of improved survival as a consequence of ICT in patients suffering from transfusional iron overload.
We have observed improvement in haematopoietic parameters in a proportion of patients with low-to-intermediate risk MDS treated with the oral iron chelator deferasirox (DFX). Our experimental results suggest that the haematopoietic response following treatment is likely to be a consequence of two distinct functions of DFX. Firstly, DFX inhibits NF-κB activity resulting in dampened inflammation in the bone marrow milieu. Secondly, iron chelation leads to mitochondrial dysfunction resulting in apoptosis of malignant clones whilst sparing normal haematopoietic stem cells. Our study provides for the first time a mechanistic basis for improved haematopoiesis in MDS patients treated with ICT.