Mutations of Chromatin and its Modifying Machineries in Malignancies

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 DESCRIPTION (provided by applicant): Our studies have focused on the characterization of the molecular functions and biochemical properties of the Set1/MLL family of proteins and how their chimeras and mutations are associated with childhood leukemia and other forms of cancer. We have also focused on the role of chromatin and transcriptional elongation machinery in the regulation of developmental gene expression and how the misregulation of their activities is associated with malignancies. Our hope is that our molecular studies will advance our understanding of the molecular mechanisms of rearrangement-based and mutation-based cancer through the epigenetic regulators. Our biochemical and molecular studies demonstrated that Set1 in yeast exists in the Set1/COMPASS complex capable of methylating lysine 4 of histone H3 (H3K4). We demonstrated that Drosophila cells possess three Set1-related proteins and mammalian cells have six Set1-related proteins all found within COMPASS-like compositions capable of methylating histone H3K4. Furthermore, given that there is almost no sequence homology between many of the MLL translocation partners, for many years, it was unclear why MLL translocations into so many unrelated genes result in the pathogenesis of leukemia. Our biochemical studies on the purification of the MLL-chimeras demonstrated that many of the MLL translocation partners are part of the same macromolecular complex we named the Super Elongation Complex (SEC). We demonstrated that the translocations of MLL within any of the subunits of SEC subunits result in the misrecruitment of SEC to the MLL target genes and in the perturbation of the transcriptional checkpoint control of these genes, triggering leukemic growth. Additionally, the recent cataloging of somatic mutations in cancer identified a large number of mutations in the components of the MLL1-4 and Set1A/B complexes in both hematological malignancies and solid tumors. However, we know very little why the COMPASS family is mutated in different cancers. Given that we have developed a fantastic set of reagents and tools over the past seventeen years towards these factors and their associated proteins, chromatin, and other chromatin modifiers in multiple model systems; my laboratory is in a very unique position to define the molecular bases of these factors' involvement in cancer pathogenesis for the purpose of targeted therapeutics. Therefore, the goals of this R35 application is the full molecular and biochemical characterization of the COMPASS family, the translocation partners within the Super Elongation Complex (SEC), and the role of chromatin itself in the regulation of gene expression and development, and how their mutations contribute to the pathogenesis of human cancer.