PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia

Activating mutations in the KIT tyrosine receptor kinase confer an adverse prognosis for patients with acute myeloid leukemia (AML). Successful treatment options are limited, as kinase inhibition monotherapy for AML is often followed by rapid drug resistance. Here we demonstrate that combined KIT and LSD1 inhibition causes increased cytotoxicity and may mitigate the propensity for relapse with kinase inhibition. This combination suppresses MYC at both the transcript and protein level to drive cell cycle exit and cell death. This decreased MYC transcript expression results from a loss of PU.1 binding at a downstream MYC enhancer leading to decreased acetylation at the MYC enhancer and promoter. Additionally, the drug combination inactivates PI3K/AKT/GSK3 signaling to decrease MYC protein stability. Within 24 hours, KIT-mutant AML cells adapt to KIT inhibitor monotherapy by restoring PI3K/AKT activity. However, with the addition of a LSD1 inhibitor, PI3K/AKT activity cannot be restored. Taken together, KIT and LSD1 inhibition cooperatively target MYC activity through altered transcription and modulation of signaling to drive a lasting response. In addition, we validate MYC suppression as a mechanism of synergy between KIT and LSD1 inhibition in KIT-mutant AML patient samples. Collectively, this work provides rational for a clinical trial to assess the efficacy of KIT and LSD1 inhibition in patients with KIT-mutant AML.