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

Abstract Leukemic stem cells (LSC) 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. In this study, we showed that SETD8, a lysine methyltransferase that monomethylates lysine 20 of histone H4, is essential for the maintenance of stemness in t(8;21) AML LSCs. Genetic deletion or pharmacologic 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 Ras homolog family member T1 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. Significance: SETD8 increases enhancer chromatin accessibility and expression of RHOT1 to reprogram mitochondrial homeostasis and support leukemia stem cells, indicating that SETD8 may be a druggable target for acute myeloid leukemia.