Simultaneous perturbation of epigenetic and signaling pathways synergistically induces therapeutic differentiation of acute myeloid leukemia

While most current therapies for acute myeloid leukemia (AML) suffer from limited efficacy and substantial toxicity, differentiation therapy has proven to be curative for the rare AML subtype, acute promyelocytic leukemia (APL). However, whether differentiation induction is a generalizable therapeutic approach for AML and beyond remains incompletely understood. In this study, we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the Wnt pathway GSK3? kinase (GSK3?i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumor burden in a xenograft mouse model. Mechanistically, this combination treatment induces selective co-occupancy of IRF7 and -catenin at promoters of the type I interferon signaling pathway component genes such as STAT1 essential for AML differentiation, and key downstream target genes, and consequently their expression. Combination treatment also appears to suppress the canonical, pro-oncogenic Wnt pathway. Importantly, analysis of AML patient datasets suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, our findings suggest that this combination strategy may potentially re-route transcriptional programs to favor differentiation, which may have important therapeutic implications for AML and Wnt-driven cancers beyond AML.