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

Massett, M. E. et al. (2021) A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival. Cell Death and Disease, 12(6), 573. (doi: 10.1038/s41419-021-03738-0) (PMID:34083515) (PMCID:PMC8175737)

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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.

Item Type:Articles
Additional Information:This work was supported by the Wellcome Trust [105614/Z/14/Z]; Leuka [2016/JGF/0005]; the Howat Foundation and Friends of Paul O’Gorman; Chief Scientific Office (CSO) [CGA/19/63]; MRC CiC [18048]; Tenovus Scotland [S19-13] and SULSA-PECRE; XH is a John Goldman Fellow; MM is a recipient of Medical Research Council (MRC), UK DTP PhD studentship [1732424]; LM is a recipient of Adam Renwick Martin-Friends of Paul O’Gorman PhD Studentship; SP is a recipient of Carnegie Trust PhD Studentship [PHD007721].
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert and Bunschoten, Mr Roderick and Massett, Mr Matthew and Vetrie, Professor David and Jorgensen, Dr Heather and Michie, Dr Alison and Patterson, Mr Shaun and Hoose, Mr Alex and Huang, Dr Xu and Mannion, Dr Niamh and Monaghan, Miss Laura
Authors: Massett, M. E., Monaghan, L., Patterson, S., Mannion, N., Bunschoten, R. P., Hoose, A., Marmiroli, S., Liskamp, R. M.J., Jørgensen, H. G., Vetrie, D., Michie, A. M., and Huang, X.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Science and Engineering > School of Chemistry
Journal Name:Cell Death and Disease
Publisher:Springer Nature
ISSN:2041-4889
ISSN (Online):2041-4889
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cell Death and Disease 12(6): 573
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172121Funding SchemesAnna DominiczakWellcome Trust (WELLCOTR)105614/Z/14/ZInstitute of Cardiovascular & Medical Sciences
173450Delineation of the critical epigenetic regulatory machinery selective for acute myeloid leukaemia stem cell functionXu HuangLeuka (LEUKA)2016/JGF/0005CS - Paul O'Gorman Leukaemia Research Centre
308928Identification of combination therapies targeting DNA damage repair signalling pathways in acute myeloid leukaemia (AML) stem cellsXu HuangOffice of the Chief Scientific Adviser (CSO)CGA/19/63CS - Paul O'Gorman Leukaemia Research Centre
306054Confidence in Concept 2019Anna DominiczakMedical Research Council (MRC)MC_PC_18048MVLS - College Senior Management
307974PROJECT S19-13 - A pre-clinical study to validate an epigenetic based therapy for precision medicine of acute myeloid leukaemia (AML)Xu HuangTenovus Scotland (TENOVUS)S19-13CS - Paul O'Gorman Leukaemia Research Centre