Abstract
Epigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.
Highlights
Epigenetic regulators are frequently mutated in acute myeloid leukemia (AML), leading to epigenomic alterations[1]
KDM4A expression is unique (Fig. S1B) being highly enriched in AML-leukemia stem cell (LSC)+ populations (Fig. S1C), suggesting that KDM4A is important for LSC, which are negatively correlated with AML patient survival
Previous reports indicate that the KDM4 family is required for normal hematopoiesis[9,35], whilst loss of individual members is tolerated in normal cells[35] highlighting the importance of identifying KDM4 family members that are essential for the survival of AML cells
Summary
Epigenetic regulators are frequently mutated in acute myeloid leukemia (AML), leading to epigenomic alterations[1]. Inhibitors that target epigenetic modulators to rectify epigenomic abnormalities represent valid therapeutic strategies. Further understanding of how epigenetic dysregulation in AML contributes to leukemogenesis may uncover tractable therapeutic targets and biomarkers for AML patient treatment and/or prognostic evaluation. Primary AML blasts from patients with poor prognosis feature global H3K9me[3] hypomethylation[7] positing an oncogenic role for H3K9me[3] demethylases in AML. Cheung et al identified an H3K9me[3] demethylase, KDM4C as a cofactor of the PRMT1 complex in MLL rearranged (MLLr) and MOZ-TIF2 AML8. Simultaneous knockout (KO) of all three members of the Kdm[4] family (kdm4a/b/c) in mice attenuates MLL-AF9 AML9, indicating roles for the Kdm[4] family in murine myeloid leukemia. The therapeutic benefit of targeting the KDM4 family in human AML is not well understood
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