Ikaros-based epigenetic regulation of T cell leukemogenesis

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DESCRIPTION (provided by applicant): The DNA binding factor Ikaros and its chromatin remodeling associates of the Nucleosome Remodeling and Deacetylase (NuRD) complex control many key aspects of T cell differentiation and function providing us with a formidable entry point into the epigenetic regulation of this developmental process. Breakdown in this Ikaros-based epigenetic machinery interferes with T cell maturation and result in rapid development of T cell leukemia demarcated by activation of Notch signaling. This process and the mechanisms involved are the focus of our current investigation. In aim 1, we test the role of Ikaros in setting chromatin environments by examining the cause-effect relationship between Ikaros-loss-of-function and the epigenetic changes manifested in its immediate neighborhood as well as the transcriptional changes that follow. Several important insights are to be gleaned here, such as the role of Ikaros in setting epigenetic code, in regulating gene networks and signaling pathways that control normal development and how these are subverted for leukemia development. We also test whether a change in the potential for leukemia development seen during T cell maturation is due to a change in Ikaros gene targets or in their epigenetic state and mode of regulation. In aim 2, we go deeper into the central mechanism by which Ikaros regulates chromatin accessibility. We test Ikaros' antagonism with its chromatin remodeling associate, Mi-22, in dictating local nucleosome dynamics and histone modifications at their sites of action and the role of Ikaros' DNA binding in this process. We examine whether Ikaros promotes or inhibits access to other factors that also target its immediate neighborhood. The role of signaling pathways activated in T-ALL in targeting Ikaros' DNA binding through post-translational modifications is investigated as a potential key to altering the chromatin remodeling output of the NuRD complex to achieve rapid changes in gene expression during development. The Ikaros-based epigenetic mechanisms and the functional gene networks they control, deduced from our proposed studies will provide the means to manipulate both normal and aberrant stages of T cell differentiation. Importantly, these studies may in the future empower the design of intelligent/tailored therapies for T-ALL treatment.