Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia.

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 super-enhancer, suppressing super-enhancer 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 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 super-enhancer complex

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu