Loss of SETD8 Impairs Mitochondrial Homeostasis to Suppress Leukemia Stem Cell Function in t(8;21) Acute Myeloid Leukemia

Abstract Leukemic stem cells (LSCs) contribute to relapse and resistance in patients with t(8;21) acute myeloid leukemia (AML). Chromatin accessibility remodeled by epigenetic alterations represents a defining hallmark of LSCs that endows them with enhanced survival and self-renewal capacities, which may offer potential therapeutic opportunities for intervention. Here, we showed that SETD8, a lysine methyltransferase that monomethylates lysine 20 of histone H4 (H4K20me1), is essential for the maintenance of stemness in t(8;21) AML LSCs. Genetic deletion or pharmacological inhibition of SETD8 impaired the survival and self-renewal of LSCs in retroviral AML1-ETO9a-driven t(8;21) AML mice and primary t(8;21) AML CD34+ cells. Mechanistically, SETD8 promoted the expression of the mitochondrial outer membrane protein RHOT1 by increasing chromatin accessibility at the enhancer region, thereby reprogramming mitochondrial homeostasis. These findings improve our understanding of gene regulation through chromatin accessibility remodeling and establish a link between histone lysine methylation and mitochondrial homeostasis, suggesting a potential strategy for eliminating LSCs in t(8;21) AML.