Patients with low-grade myelodysplastic syndromes (MDS) show high levels of tumor necrosis factor α (TNFα) and up-regulation of apoptosis in the marrow. In contrast, marrow cells in advanced MDS are typically resistant to TNFα-induced apoptosis but are rendered apoptosis-sensitive on coculture with stroma. The present studies show that CD34(+) marrow cells in advanced MDS express high levels of TWIST, a basic helix-loop-helix transcription factor that opposes p53 function. TWIST levels correlated with disease stage (advanced > low grade; P = .01). Coculture with HS5 stroma resulted in down-regulation of TWIST and increased apoptosis in response to TNFα in CD34(+) cells from advanced MDS; the same effect was achieved by TWIST-specific RNA interference in CD34(+) cells. In primary MDS marrow stroma TWIST expression was lower than in healthy controls; suppression of TWIST in stroma interfered with induction of apoptosis sensitivity in cocultured CD34(+) cells. Stroma cells so modified expressed reduced levels of intercellular adhesion molecule-1 (ICAM1; CD54); blockade of ICAM1 in unmodified stroma was associated with reduced apoptosis in cocultured CD34(+) MDS marrow cells. These data suggest role for dysregulation of TWIST in the pathophysiology of MDS. Conceivably, TWIST or components in the signaling pathway could serve as therapeutic targets for patients with MDS.