Mechanism and therapeutic opportunities of targeting the Tudor domain

PROJECT SUMMARY/ABSTRACT MLL-rearranged (MLL-r) leukemias account for 5-10% of human acute leukemia and is associated with poor prognosis. The unmet clinical needs and the lack of an effective targeted therapy to the MLL-r leukemias emphasize the need for novel regimens. Recent cancer epigenetics studies discovered a central role for the histone H3 lysine 79 (H3K79) methyltransferase DOT1L in MLL-r leukemogenesis. Important clinical responses have been noted with DOT1L inhibitor treatment as a single agent, however, it is expected that combination treatments will be necessary. Our preliminary studies based on a Tudor domain focused CRISPR screen in MLL-r leukemia identified SGF29 as a novel vulnerability in MLL-r leukemia. The objective of this application is to determine the critical epigenetic mechanisms that mediate the availability of KAT2A/B to maintain H3K9ac and oncogene expression in MLL-r leukemia. Our central hypothesis is that SGF29, an H3K4me3 reader protein, mediates recruitment of KAT2A/B to maintain histone H3K9ac and MYC oncogenic program in MLL-r leukemia. We will dissect the SGF29-mediated epigenetic mechanisms (Aim 1) and investigate the efficacy of SGF29 targeting (alone or in combination with DOT1L inhibition) as a novel therapy in MLL-r leukemia (Aim 2). This study is innovative because (1) it introduces a novel concept of simultaneously targeting multiple components of an epigenetic network to efficiently suppress the cancer programs, and (2) it establishes a brand new genetic screen approach for a sub-protein level functional pocket and drug discovery. The impact of this research will be of significance because (1) it immediately provides novel therapeutic opportunities against the difficult-to-treat MLL-r leukemias, and (2) it will help identify novel functional elements in epigenetic regulators for future pharmaceutical targeting.