The pathogenesis of myelodysplastic syndromes (MDS)

The term myelodysplastic syndromes (MDS) summarizes a range of different haematological disorders, which display peripheral cytopenia as common clinical characteristic. This 'ineffective haematopoiesis' is thought to be a result of an imbalance of apoptotic and proliferative signals in bone marrow cells. In early MDS, there is increased apoptosis among bone marrow haematopoietic cells, which is partially due to upregulation of TNF-alpha and death-receptors, including FAS and TRAIL-R, and also to decreased expression of anti-apoptotic molecules. Immune-mediated attack by clonal T cells may also be responsible for the clinical presentation in MDS subgroups. Apart from macrophages, bone marrow stromal cells do not appear to have clonal characteristics, although stromal cell interaction with haematopoietic cells seems to be disturbed. In advanced MDS, excessive concentrations of VEGF and microvessel density have been associated with increased angiogenesis. Certain tumor suppressor genes have hypermethylated, and thereby silenced, promoters, some of which might respond to hypomethylating agents. Other molecules, including p38 and heat shock proteins, recently implicated in the pathogenesis of MDS, might in the future serve as new molecular targets in the treatment of MDS. Additionally, new techniques will further allow us to get more insights into this complex disease, which wilt result in individualized treatment algorithms. (C) 2007 Elsevier Ltd. All rights reserved.