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Loss of SETD8 remodels enhancer chromatin accessibility to eliminate t(8;21) leukemia stem cells by mitochondrial homeostasis reprogramming [CUT&Tag (H3K27ac)]

ABSTRACT: Leukemic stem cells (LSCs) are at least partially responsible for relapse and resistance in patients with t(8;21) acute myeloid leukemia (AML), while the intricate regulatory network governing LSC stemness is yet to be fully elucidated. Chromatin accessibility remodeled by epigenetic alterations represents a defining hallmark of LSCs, endowing them with enhanced survival and self-renewal capacities, which may offer potential therapeutic opportunities for intervention. Here, we show 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 impairs 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 promotes the expression of Ras homolog family member T1 (RHOT1), a mitochondrial outer membrane protein, by increasing chromatin accessibility at the enhancer region, thereby reprogramming mitochondrial homeostasis. These findings improve our understanding of the 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285586 | GEO | 2025/08/06

REPOSITORIES: GEO

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Project description:The t(8;21) translocation fuses the DNA binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape we measured genome-wide RUNX1- and RUNX1/ETO bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide re-distribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. This SuperSeries is composed of the following subset Series: GSE29222: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [ChIP-Seq and DNAse-Hypersensitivity data] GSE29223: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding [expression array data] GSE34540: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (ChIP-seq) GSE34594: Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding (Illumina expression) Refer to individual Series

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Loss of SETD8 remodels enhancer chromatin accessibility to eliminate t(8;21) leukemia stem cells by mitochondrial homeostasis reprogramming [CUT&Tag (H3K27ac)]

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