Molecular pathogenesis of myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorders characterized by inefficient hematopoiesis, hypercellular bone marrow, dysplasia of blood cells and cytopenias. Most patients are diagnosed in their late 60s to early 70s. MDS is a risk factor for the development of acute myeloid leukemia which can occur in 10-15% of patients with MDS. A variety of pathophysiologic mechanisms contributes to the genesis and persistence of MDS including immunologic, epigenetic, cytogenetic and genetic factors. The only potential curative option for MDS is hematopoietic cell transplantation which is suitable for only a few patients. Currently approved therapeutic options for MDS, including lenalidomide, decitabine, and 5-azacytidine, are targeted to improve transfusion requirements and quality of life. Moreover, 5-azacytidine has also been demonstrated to improve survival in some patients with higher risk MDS. New ways to predict which patients will better gain benefit from currently available therapeutic agents are the primary challenges in MDS. In the last 10 years, chromosome scanning and high throughput technologies (single nucleotide polymorphism array genotyping, comparative genomic hybridization, and whole genome/ exome sequencing) have tremendously increased our knowledge of MDS pathogenesis. Indeed, the molecular heterogeneity of MDS supports the idea of different therapeutic approaches which will take into account the diverse morphologic and clinical presentations of MDS patients rather than a restricted therapeutic strategy. This review will summarize the molecular abnormalities in key relevant components of the biology and pathogenesis of MDS and will provide an update on the clinical impact and therapeutic response in MDS patients.

Keywords: MDS; molecular mutations; pathogenesis.

Figure 1.

Schema of the diagnostic tests, classification systems, and prognostic/ scoring systems in Myelodysplastic syndromes. Microscopy, immunohistochemistry, G-banding, and sometimes flow cytometry are all useful diagnostic tests in Myelodysplastic syndromes (MDS). Prognostic markers include: bone marrow and peripheral blood morphology, numbers of blasts, morphologic features (ring sideroblasts), dysplasia, cytopenias and cytogenetic changes. Classification systems include (FAB, 2002 and 2008 WHO). Risk stratification scoring systems have been created for de novo MDS with and without account for cytogenetic findings. Abbreviations. BM, bone marrow; LDH, lactate dehydrogenase; ALIP, abnormal localization of immature precursors; MC, metaphase cytogenetics; FAB, French American British Classification; IPSS, International prognostic scoring system; WPSS, WHO classification-based Prognostic Scoring System; IPSS-R: International prognostic scoring system-Revised.