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

ABSTRACT: Responses to kinase-inhibitor therapy in AML are frequently short-lived due to the rapid development of resistance, limiting the clinical efficacy. Combination therapy may improve initial therapeutic responses by targeting pathways used by leukemia cells to escape monotherapy. Here we report that combined inhibition of KIT and lysine-specific demethylase 1 (LSD1) produces synergistic cell death in KIT-mutant AML cell lines and primary patient samples. This drug combination evicts both MYC and PU.1 from chromatin driving cell cycle exit. Using a live cell biosensor for AKT activity, we identify early adaptive changes in kinase signaling following KIT inhibition that are reversed with the addition of LSD1 inhibitor via modulation of the GSK3a/b axis. Multi-omic analyses, including scRNA-seq,

SUBMITTER: Curtiss BM 

PROVIDER: S-EPMC9256806 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature