Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia

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. Implications: 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.

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

“…Although the synergistic effects of LSD1 inhibitors and other protein inhibitors, such as BRD4 and NAE, have been confirmed, there have not been multitarget drugs based on LSD1 and other proteins. Here, we summarize the combined application of LSD1 inhibitors with other targeted drugs, ,− hoping to provide theoretical guidance for the development of multitarget drugs.…”

“…133 In 2023, Yashar et al reported that combining an LSD1 inhibitor GSK-2879552 and an FLT3 inhibitor Quizartinib exhibited a synergistic effect in inducing cell death in FLT3 mutant AML (Table 2). 101 This drug combination simultaneously disrupted the binding of STAT5, LSD1, and GFI1 from the MYC blood superenhancer complex, leading to the repression of MYC expression and causing the accumulation of repressive H3K9me1 at MYC target genes.…”

Predicting transcription factor activity using prior biological information

“…Notably, in a different study, we have applied a preliminary version of Priori to investigate the mechanism of combined FLT3 and LSD1 inhibition in FLT3-ITD AML. 64 We used Priori to identify important determinants of the drug combination response and showed that predicted activity of a putative drug combination target, MYC , decreased in six patient samples. Since Priori scores are normalized across all samples analyzed within the same run, we expect that Priori has more power to identify differences in transcription factor activity among larger patient cohorts.…”