A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival
Open Access
- 3 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (6), 1-16
- https://doi.org/10.1038/s41419-021-03738-0
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.Keywords
Funding Information
- Adam Renwick Martin-Friends of Paul O’Gorman PhD Studentship
- Carnegie Trust for the Universities of Scotland (PHD007721)
- RCUK | Medical Research Council (1732414, 18048)
- Chief Scientist Office (CGA/19/63)
- Tenovus (S19-13)
- Wellcome Trust (105614/Z/14/Z)
- Leuka (2016/JGF/0005)
- Friends of Paul O'Gorman Leukaemia Research Centre Howat Foundation
This publication has 38 references indexed in Scilit:
- The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem CellsCancer Cell, 2012
- RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemiaNature, 2011
- Quantitative High-Throughput Screening Identifies 8-Hydroxyquinolines as Cell-Active Histone Demethylase InhibitorsPLOS ONE, 2010
- Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemiaBlood, 2010
- The PAF Complex Synergizes with MLL Fusion Proteins at HOX Loci to Promote LeukemogenesisCancer Cell, 2010
- The Human PAF1 Complex Acts in Chromatin Transcription Elongation Both Independently and Cooperatively with SII/TFIISCell, 2010
- HOXA9 is required for survival in human MLL-rearranged acute leukemiasBlood, 2009
- WGCNA: an R package for weighted correlation network analysisBMC Bioinformatics, 2008
- Reversal of Histone Lysine Trimethylation by the JMJD2 Family of Histone DemethylasesCell, 2006
- A Stem Cell Molecular SignatureScience, 2002