Mutations of Chromatin and its Modifying Machineries in Malignancies

点击翻译按钮获取中文摘要

Project Summary Collective studies from my laboratory have focused on the molecular characterization of the function(s) and biochemical properties of the epigenetic modifiers and the mutations that are associated with human cancer. Our goal has been to determine how the mutations in these factors molecularly change the pattern of gene expression resulting in cellular hyperproliferation and use these molecular pathways to identify targeted therapeutics for cancer. Our detailed structural studies supported during the past seven years by this grant R35CA197569 have allowed us to identify the atomic structure of Set1/COMPASS, and based on this information, we have generated inhibitors towards its activity that are now being developed in our laboratory as a tool compound to regulate COMPASS's function in cells for the ultimate use in clinic. On other fronts, our analyses of the role of MLL3/COMPASS identified its interactions with the histone deubiquitinating enzyme BAP1, providing a central epigenetic balance at enhancers and the regulation of gene expression in cancer caused as the result of MLL3 mutations. Based on this information, we have a clinical trial at Northwestern Medicine investigating the epigenetic role of this balance in cancer therapy. We have also generated BAP1 inhibitors that can regulate hyperactivated BAP1 function in cancers caused as the result of ASXL1 mutations and such BAP1 inhibitors are being further investigated in our laboratory as biochemical and clinical tools. Our detailed analysis of the role of histone H3K27M mutations in diffuse intrinsic pontine gliomas (DIPG) resulted in the identification of a role for BET-domain containing factors such as Brd2 and Brd4 in DIPG pathogenesis. We are collaborating with colleagues at Lurie Children's Hospital of Chicago to test these findings in clinic. These studies also resulted in the identification of CATACOMB as an endogenous factor mimicking H3K27M and regulating PRC2 function. As will be described in the application, other studies in the laboratory have probed the mechanistic properties of diverse epigenetic factors in developmental regulation and in cancer. Additionally, recent cataloging of somatic mutations in cancer and during natural aging has identified a large number of mutations in the components of the MLL1-4, UTX, Set1A/B, and other epigenetic factors. Given that we have developed a fantastic set of reagents and tools over the past twenty years in our laboratory towards these factors, their associated proteins, chromatin, and other chromatin modifiers in multiple model systems, my laboratory is in a very unique and strong position to define the molecular bases of these factors’ involvement in cancer pathogenesis, and thus, for the purpose of targeted therapeutics. The goals of this R35 renewal application are the continuation of our full molecular and biochemical characterization of the trithorax COMPASS family and BAP1 complexes in the regulation of developmental gene expression, and how their mutations contribute to the pathogenesis of human cancer.