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 Michie, Professor Alison and Hoose, Mr Alex and Huang, Dr Xu and Monaghan, Miss Laura and Vetrie, Professor David and Jorgensen, Dr Heather and Patterson, Mr Shaun and Mannion, Dr Niamh |
| 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 > School 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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