Pathogenetic aspects of MDS: the role of apoptosis

Haema 2011; 2(2): 153-161

by Agapi Parcharidou1, Panagiota Tsoplou2, Αrgiris Symeonidis3

13rd Dept of Internal Medicine, Korgialeneio-Benakeio Hospital of Athens,
2BIOIATRIKI Laboratories, Dept of Human Genetics, Athens,
3Hematology Division, Dept of Internal Medicine, University of Patras Medical School, Patras.

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Myelodysplastic syndromes (MDS) have traditionally been classified on the basis of clinical and morphological criteria. Despite many similarities, there is substantial heterogeneity among these syndromes, such as peripheral blood cytopenias, clonal hematopoiesis and evolution to acute myelogenous leukemia (AML). Recent insight however, has shown that they result from defects of both, a hematopoietic stem-cell and of the bone marrow microenvironment. A common and dominant feature is the detection of increased progenitor cell apoptosis, as a result of various autocrine and paracrine facsigtors, elaborating in the bone marrow, implicating both, seed (stem cells) and soil (bone marrow stroma) in the pathophysiology of these disorders. Pro-inflammatory cytokines in the marrow microenvironment, and particularly TNF-α, are the main paracrine mediators of apoptosis, but the mechanisms of the clonal cells’ suicide process have remained a mystery for decades. It has recently been shown that the ribosomal biogenesis can initiate a stress response in the cell, through the p53 signaling pathway, as a result of mutations/deletions of the ribosomal protein genes in a similar way with some congenital anemias. Surprisingly, it was found that patients with the Del-5q syndrome exhibit haplo-insufficiency of the ribosomal protein gene RPS14, which appears to participate substantially in the pathogenesis of anemia in this MDS subtype. Similar ribosomal deregulation has also been found in other categories of MDS, rendering this finding an additional unique feature of MDS. In addition to these findings, there are other DNA-related abnormalities such as uniparental disomy, mutations in the TET2 gene, and epigenetic phenomena, as well as mitochondrial malfunction and damage, associated with elevated intracellular oxidative stress, which can be observed across all types of MDS. This review summarizes the pathogenetic aspects in relation to apoptosis which are observed in this heterogeneous group of diseases.