Pathogenesis Model

The occurrence of MDS is best viewed in the framework of a multi-hit theory. Hereditary and multiple environmental factors result in a neoplastic stem cell clone.7 The MDS clone is characterized by altered gene functions; the gene alterations result either from single-gene mutations, chromosomal abnormalities (mostly deletions), or gene silencing. Many of those altered genes are suppressor genes that function in a recessive manner. Various gene alterations of MDS clone result in an intrinsic increase in the susceptibility of the clone to apoptosis. MDS clone is also recognized by the immune system leading, in some cases, to clonal T-cell proliferation that leads to release of various cytokines, including TNF alpha.8-10 The cytokines cause the apoptosis of the MDS clone and of normal hematopoietic cells.11 This intrinsic and immune-mediated susceptibility to apop-tosis are the hallmarks of early MDS pathogenesis, explaining the clinical findings of peripheral cytopenias despite a hypercellular bone marrow.12

0 0

Post a comment