Strategies for biology- and molecular-based treatment of myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) constitute a group of clonal stem cell disorders characterized by cytopenia, ineffective hematopoiesis, bone marrow dysplasia, and a risk of progression to acute myeloid leukemia (AML). Disease mechanisms can be divided into two main groups; those underlying the increased apoptosis of bone marrow progenitors, and those associated with progressive blast proliferation, and transformation to acute myeloid leukemia. The recently published WHO classification includes one subtype with a specific cytogenetic lesion, the 5q- syndrome, but otherwise classification of MDS is based solely on clinical and morphological criteria. Subsequently, few therapeutic options have been directed towards specific biological or molecular mechanisms in MDS. Progenitor apoptosis in MDS may be initiated by extrinsic and intrinsic mechanisms. The extrinsic pathway includes T-cell mediated bone marrow failure, for which antithymocyte globulin treatment may be an effective, as well as negative effects caused by the marrow microenvironment. New therapeutic options targeting the microenvironment include thalidomide and its analogue, lenalidomide, which has proven extremely effective for patients with 5q- syndrome. The erythroid apoptosis of in particular sideroblastic anemia is mediated by mitochondrial release of cytochrome c, which may be inhibited by treatment with erythropoietin and granulocyte-colony-stimulating-factor. Important mechanisms for disease progression are DNA hypermethylation, histone deacetylation, and possibly RAS mutations. Two new DNA hypomethylating agents, azacytidine and decitabine, have shown efficacy in patients with high-risk MDS, and may prolong time to progression. In conclusion, recent advances in the pathogenetic understanding of MDS have led to significant therapeutic progress.