(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Myelodysplastic Syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases, resulting predominantly from acquisition of somatic mutations in hematopoietic stem/progenitor cells (HSPC), which cause ineffective hematopoiesis, cytopenias, and possible progression to leukemia. The acquired and germline genomic alterations impact genes in diverse biological pathways, globally modifying gene expression or genomic integrity, including epigenetic regulation, RNA splicing, DNA repair, and transcription. At present a comprehensive understanding of biology promoting the development, progression and MDS resistance to therapy is lacking. One major obstacle for advancing our understanding of MDS biology has been the paucity of informative disease models. In this proposal we will develop critical resources for investigators pursuing MDS research including a) key information, a ‘roadmap’, of the mutational architecture of MDS; b) a repository of induced pluripotent stem cell (iPSC)-derived MDS HSPC cell lines; c) a comprehensive resource containing molecularly-defined drug sensitivities for MDS linked to key clinical data; d) a catalogue of novel antigenic targets and models to advance adoptive T cell immunotherapy for MDS patients. This research will enable a more rational approach to developing specific treatment strategies and predicting patient outcomes. The proposed studies will use a unique, large cohort of MDS marrow samples from a diverse population of patients with comprehensive clinical and genomic annotations. In Aim 1, we will reprogram MDS cells into iPSC, generating a panel of cell lines based on patient genotypes, and employ iPSCs and molecular data to reconstruct clonal histories and assess the functional consequence of mutation order. Aim 2 will focus on the functional consequences of MDS mutations, using a platform that integrates mutations, gene expression, and high-throughput sensitivity screens employing a large custom panel of drugs, targeted inhibitors, and combinations rationally designed for this disease. In Aim 3, we will use MDS primary samples and iPSC lines to perform proteomic analysis, linking mutational and proteomic data to discover potential new target antigens for T cell immunotherapies, permissive for normal hematopoiesis while eradicating MDS progenitors. Our proposed collaborative and synergistic studies will advance our understanding of the path from mutational perturbation to functional consequences in MDS and create a library of resources that can be shared with the greater MDS scientific community to enable further progress toward improved treatment strategies.