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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 Vβ 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 Vβ 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.
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