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 DOT1L-inhibitor sensitization screen in MLL-r leukemia have identified suppression of BAZ2A significantly increases the anti-leukemic activity of the DOT1L inhibitor. The objective of this application is to determine the critical epigenetic mechanisms that mediate the availability of SIRT1 to suppress oncogene expression in MLL-r leukemia. Our central hypothesis is that BAZ2A, a chromatin remodeling protein of rDNA loci, mediates redistribution of SIRT1 for histone deacetylation and silencing of MLL-r/DOT1L-driven oncogene. We will dissect the BAZ2A/SIRT1 chromatin targeting mechanisms (Aim 1), investigate the efficacy of DOT1L and BAZ2A combination therapies (Aim 2), and validate a novel saturation CRISPR protein scan technology for de novo discovery of the functional elements in DOT1L and BAZ2A (Aim 3). 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 domain 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.
MLL-rearrangement (MLL-r) affects about 10% acute leukemia patients and is associated with poor prognosis. This proposal has immediate clinical relevance in developing a more advanced treatment to MLL-r leukemias, and will contribute to a broader understanding of how the dynamic epigenetic networks control oncogene expression in cancers and therapeutic responses. The technology developed in this project will facilitate functional domain discovery for future targeted therapies.
