A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival

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 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 down-regulation 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.

Role of the Paf1 complex in the maintenance of stem cell pluripotency and development

“…The KDM4A‐Paf1 regulatory network showed a significantly high association with LSC activity [64]. For instance, in the Kaplan–Meier survival analysis, AML patients with high expression levels of both KDM4A and PAF1 were reported to have a shortened overall survival rate [64]. Although the specific mechanisms of their association are unknown, it is evident that Paf1C subunits might impart stem‐cell‐like properties to pancreatic, ovarian and blood cancer cells.…”

“…Indeed, recent research has illustrated a correlation between histone demethylase (KDM4A), Paf1 and LSC activities. ChIP-seq data revealed many overlapping binding sites between KDM4A and PAF1 as well as between differentially expressed (DE) genes of KDM4A KD and PAF1 KD [64]. The KDM4A-Paf1 regulatory network showed a significantly high association with LSC activity [64].…”

“…ChIP-seq data revealed many overlapping binding sites between KDM4A and PAF1 as well as between differentially expressed (DE) genes of KDM4A KD and PAF1 KD [64]. The KDM4A-Paf1 regulatory network showed a significantly high association with LSC activity [64]. For instance, in the Kaplan-Meier survival analysis, AML patients with high expression levels of both KDM4A and PAF1 were reported to have a shortened overall survival rate [64].…”