Model of disease evolution in MDS.Upper panel: risk factors commonly associated with the development of myeloid disorders (germline variants, smoking, aging, and cancer treatment exposure such as chemo/radiotherapy). Middle panel: a hypothetical model of clonal evolution in which the founding event (or germline predisposition lesion) leads to subsequent acquisition/loss of new somatic mutations in a linear/branching fashion. Lower panel: the typical acquisition of methylation during MDS progression, which leads to the silencing of genes such as tumor suppressor and the disruption of many cell pathways (DNA repair, apoptosis, cell cycle, cell adherence).