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posted on 2023-07-05, 08:40 authored by William M. Yashar, Brittany M. Curtiss, Daniel J. Coleman, Jake VanCampen, Garth Kong, Jommel Macaraeg, Joseph Estabrook, Emek Demir, Nicola Long, Daniel Bottomly, Shannon K. McWeeney, Jeffrey W. Tyner, Brian J. Druker, Julia E. Maxson, Theodore P. Braun Log2 Normalized Counts of Differentially Expressed Genes from Primary AML Blast Bulk RNA-seq (24 Hours After Drug Treatment)
Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...American Society of Hematology (ASH)
American Cancer Society (ACS)
National Institutes of Health (NIH)
Leukemia and Lymphoma Society (LLS)
History
ARTICLE ABSTRACT
Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood superenhancer, suppressing superenhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD (internal tandem duplication) AML.
This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific superenhancer complex.
