Defining epigenetic mechanisms in NPM1c mutant leukemia

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Project Summary/Abstract Nucleophosmin (NPM1) mutations are among the most common aberrations in acute myeloid leukemia (AML) and cause a characteristic stem cell-like gene expression pattern including the upregulation of HOXA/B cluster genes and their co-factors MEIS1. The molecular mechanisms of how NPM1c mutations regulate this aberrant gene expression program remains poorly understood and there are currently no targeted therapy options available. We have recently found that NPM1c mutant leukemias depend on the histone methyltransferase MLL and its adaptor protein Menin to maintain leukemia gene expression and proliferation. The interaction between Menin and MLL is essential for the recruitment of the MLL complex to a subgroup of its target genes, such as MEIS1, which are in turn essential for maintaining leukemic self-renewal. Therapeutic targeting of the Menin- MLL interaction with small molecule inhibitors causes a loss of self-renewal and differentiation of NPM1c leukemia cells. The link between NPM1c mutations and the MLL-complex remains to be resolved. In the proposed project, we will develop a comprehensive understanding of the chromatin state that occurs in the presence of NPM1c specifically focusing on the role of Menin and MLL in this process. To achieve this, we will first determine the changes in chromatin state upon NPM1c degradation and determine essential protein domains of NPM1c (Aim 1). Next, we will identify which transcriptional activators and chromatin modifiers associate with the Menin-MLL complex in NPM1c mutant leukemias that lead to the aberrant target gene activation (Aim 2). Finally, we will focus on the chromatin binding factor LEDGF, which has been shown to associate with Menin-MLL and recruit transcriptional activators to control gene expression. Our preliminary data suggests that LEDGF is a dependency in NPM1c mutant leukemia cells and that LEDGF loss enhances the detrimental effects of Menin-inhibition on cell survival and MLL-target gene expression (Aim 3). In summary, the insights gained from the proposed project will help advance our mechanistic understanding of NPM1c driven leukemia development with the goal of improving treatment strategies in the future.