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 have identified an essential role of the PHF20/KAT8 histone acetyltransferase complex, in supporting the expression of DOT1L-driven oncogenes. The objective of this application is to determine the critical epigenetic mechanisms that collaborate with DOT1L to maintain oncogene expression in MLL-r leukemia. Our central hypothesis is that PHF20 mediates KAT8 recruitment to maintain the locus-specific histone acetylation and transcription of the DOT1L-driven leukemic program. We will investigate the efficacy of DOT1L and PHF20/KAT8 combination therapies (Aim 1), dissect the PHF20/KAT8 chromatin targeting mechanisms (Aim 2), and validate a novel high-density CRISPR protein scan technology for de novo discovery of the functional elements in DOT1L/PHF20/KAT8 (Aim 3). This study is innovative because (1) it introduces a novel concept of simultaneously targeting multiple components of an epigenetic feed-forward loop 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.

Public Health Relevance

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 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
1R37CA233691-01
Application #
9636020
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Jhappan, Chamelli
Project Start
2018-12-03
Project End
2023-11-30
Budget Start
2018-12-03
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010