Saturday, May 4, 2024
5/4/2024
PROJECT SUMMARY The mixed-lineage leukemia (MLL) gene rearrangements account for approximately 80% of infant acute lymphoblastic leukemia (ALL) and 35-50% of infant acute myeloid leukemia (AML). Patients bearing rearrangements of the MLL gene are associated with dismal prognosis and particularly poor response to standard treatments. Up-to-date, effective therapies for this subtype of fatal disease are still lacking. Molecularly, inter-chromosomal translocations of MLL lead to in frame fusions of the N-terminus of MLL to the C-terminus of various fusion partners, which are known as the “driver” lesions of the diseases. Among more than 70 MLL fusion partners, a small subset of fusions account for most leukemogenic cases. In ALL, over 90% MLL rearrangements involve only four fusion partners: AFF1, AF9, ENL, and AF10, all are components of the super elongation complex (SEC) or the complex of the histone H3K79 methyltransferase DOT1L. It is believed that these MLL fusions share a common pathway by “hijacking” SEC or the DOT1L complex to promote aberrant activation of the target genes of MLL fusions, leading to the pathogenesis of leukemias. Studies from the applicant and others have demonstrated that ENL, a stoichiometric component of SEC and the DOT1L complex, is critical for the oncogenic function of the MLL-fusions. ENL contains an evolutionally conserved YEATS domain. The applicant found that the YEATS domain of ENL functions as a reader of histone acetylation (Cell, 2014, 159:558-71). Importantly, the acetylation reading function of the YEATS domain is essential for growth and survival of the MLL-rearranged leukemic cells (Nature, 2017, 543:265-269). These key findings provide the proof of concept that targeting the YEATS domain of ENL is a potentially valuable therapeutic option in treatment of MLL-rearranged leukemias. The goal of this proposal within the scope of this FOA is to develop potent and selective inhibitors of the ENL YEATS domain. The specific aims of the proposal are to (1) conduct a high-throughput screening for ENL small-molecule inhibitors; (2) validate and evaluate candidate hits by orthogonal assays; and (3) characterize hits in cell-based assays. The inhibitors obtained from the proposed study will serve as tool compounds to study the functions and mechanisms of ENL in promoting MLL-fusion proteins in gene regulation and disease maintenance. These compounds will also provide the basis for further development of small molecules for targeted therapies of MLL-translocated leukemias. Preclinical studies suggest that BET inhibitors exhibit limited efficacy as single agents. Selective and potent ENL inhibitors provided by this project will be an important tool to test the synergistic effect of ENL and BET inhibitions, providing an innovative therapeutic strategy for the treatment of MLL-rearranged leukemias.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
