A model of MDS formation and progression. It is hypothesized that the altered differentiation programs and dysplasias pathognomonic of MDS are due to aberrant epigenetic regulation (summarized in Figure 1). These differentiation defects signal compensatory stem cell growth but also result in increased apoptosis, which explains the paradox of hypercellular marrows but peripheral cytopenias in MDS. With time, MDS cells acquire mutations that confer uncontrolled growth signals (eg, NRAS) and/or inhibited apoptosis (eg, P53). These mutations (and, possibly additional epigenetic defects) lead to the blast expansion and inhibited differentiation characteristic of the transition from MDS to AML.