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 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.

Transcriptional Regulation by the NFAT Family in Acute Myeloid Leukaemia

“…In addition to (cyto)genetic status, the AML transcriptome has been described as a tool for patient prognostication, whereby expression profiles within circulating blasts and/or LSCs can aid in the risk stratification of patients and can reveal specific mechanisms of oncogenesis [9][10][11][12]. Transcriptional regulators could be ideal therapeutic targets for AML, such that the effectors of multiple signalling pathways could be targeted simultaneously [13].…”

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

“…H3K9, H3K36, and H1.4K26 are the known main histone target of KDM4 demethylases [ 8 ]. In myeloid malignancies H3K9me 3 demethylase activity was described for KDM4A-D [ 34 , 35 , 39 , 40 , 41 , 42 ]. For KDM4A and KDM4C additional activity was observed towards H3K27me 3 [ 35 , 40 ].…”

Editorial: Special Issue on Innovative Multi-Disciplinary Approaches for Precision Studies in Leukemia

“…By investigating the role of recurrent mutations, epigenetic modifications and aberrant activation of oncogenic signaling (1)(2)(3)(4), our understanding of leukemogenesis has advanced to the stage that precision medicine is capable of transforming diagnostic and therapeutic approaches. This Research Topic focuses on the innovative technologies that will aid in the development of a multidimensional integrated molecular network, enabling the prediction of therapy responses and creation of novel treatments for those in most clinical need.…”

“…Our work has identified a gene signature associated with the histone demethylase KDM4A, the KDM4A-9 score, which is associated with poor OS and independent of age, cytogenetic risk and mutation status (2). KDM4A-9 is highly correlative with the LSC17 score, while having no overlap, showing the collective power of integrating risk scoring systems (2,5). In this Research Topic, risk stratification was addressed by Lu et al through bioinformatic analysis of the publicly-available databases.…”