MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. In this paper, Verma and co-workers demonstrate that smad2, a downstream mediator of transforming growth factor-beta (TGF-b) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34(+) cells, providing direct evidence of overactivation of TGF-b pathway in this disease. Suppression of the TGF- b signaling led to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI suppressed smad2 activation in hematopoietic progenitors, suppressed TGF-beta-mediated gene activation in BM stromal cells, and reversed TGF-b-mediated cell-cycle arrest in BM CD34(+) cells. This agent alleviated anemia and stimulated hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-b1. Moreover, in vitro pharmacologic inhibition of TBRI kinase led to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-b signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.