To wilms tumor protein ( wt 1 ) in myelodysplasia responsive to immunosuppressive therapy ( ist )

Clinical observations and laboratory evidence link bone marrow failure in myelodysplastic syndrome (MDS) to a T cell-mediated immune process that is responsive to immunosuppressive treatment (IST) in some patients. We previously reported that trisomy 8 MDS was more likely to respond to IST and was associated with skewed T cell receptor V profiles with clonally expanded CD8+ T cells capable of suppressing the growth of aneuploid progenitor cells in vitro. Furthermore, microarray analyses showed that Wilms tumor protein (WT1) was over-expressed by trisomy 8 hematopoietic progenitor (CD34+) cells as compared to CD34+ cells from healthy donors. Here we show that WT1 mRNA expression is upregulated by as much as 1,000-fold in the bone marrow mononuclear cells (BMMNC) of MDS patients with trisomy 8 (p = 0.001); WT1 protein levels were also significantly elevated. In addition, using a combination of physical and functional assays to detect the presence and biological reactivity of specific T cells respectively, we demonstrate that IST-responsive MDS patients exhibit significant CD4+ and CD8+ T cell responses directed against WT1. Finally WT1-specific CD8+ T cells are present within expanded V subfamilies and can inhibit hematopoiesis when added to autologous patient bone marrow cells in culture. Thus, our results strongly implicate WT1 as one of the antigens that triggers T cell-mediated myelosuppression in MDS. 2 N at ur e P re ce di ng s : h dl :1 01 01 /n pr e. 20 10 .4 15 4. 1 : P os te d 12 J an 2 01 0