KDM4B promotes acute myeloid leukemia associated with AML1-ETO by regulating chromatin accessibility.
Autor: | Ueda T; Department of Biochemistry Kindai University Faculty of Medicine Osakasayama Japan.; Graduate School of Medical Sciences Kindai University Faculty of Medicine Osakasayama Japan., Kanai A; Department of Molecular Oncology Research Institute for Radiation Biology and Medicine Hiroshima University Hiroshima Japan., Komuro A; Department of Biochemistry Kindai University Faculty of Medicine Osakasayama Japan., Amano H; Department of Biochemistry Kindai University Faculty of Medicine Osakasayama Japan., Ota K; Department of Biochemistry Kindai University Faculty of Medicine Osakasayama Japan., Honda M; Department of Biochemistry Kindai University Faculty of Medicine Osakasayama Japan., Kawazu M; Division of Cellular Signaling National Cancer Center Research Institute Tokyo Japan., Okada H; Department of Biochemistry Kindai University Faculty of Medicine Osakasayama Japan.; Graduate School of Medical Sciences Kindai University Faculty of Medicine Osakasayama Japan.; Anti-Aging Center Kindai University Higashi-Osaka Japan. |
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Jazyk: | angličtina |
Zdroj: | FASEB bioAdvances [FASEB Bioadv] 2021 Sep 12; Vol. 3 (12), pp. 1020-1033. Date of Electronic Publication: 2021 Sep 12 (Print Publication: 2021). |
DOI: | 10.1096/fba.2021-00030 |
Abstrakt: | Epigenetic alterations of chromatin structure affect chromatin accessibility and collaborate with genetic alterations in the development of cancer. Lysine demethylase 4B (KDM4B) has been identified as a JmjC domain-containing epigenetic modifier that possesses histone demethylase activity. Although recent studies have demonstrated that KDM4B positively regulates the pathogenesis of multiple types of solid tumors, the tissue specificity and context dependency have not been fully elucidated. In this study, we investigated gene expression profiles established from clinical samples and found that KDM4B is elevated specifically in acute myeloid leukemia (AML) associated with chromosomal translocation 8;21 [t(8;21)], which results in a fusion of the AML1 and the eight-twenty-one ( ETO ) genes to generate a leukemia oncogene, AML1-ETO fusion transcription factor. Short hairpin RNA-mediated KDM4B silencing significantly reduced cell proliferation in t(8;21)-positive AML cell lines. Meanwhile, KDM4B silencing suppressed the expression of AML1-ETO-inducible genes, and consistently perturbed chromatin accessibility of AML1-ETO-binding sites involving altered active enhancer marks and functional cis-regulatory elements. Notably, transduction of murine KDM4B orthologue mutants followed by KDM4B silencing demonstrated a requirement of methylated-histone binding modules for a proliferative surge. To address the role of KDM4B in leukemia development, we further generated and analyzed Kdm4b conditional knockout mice. As a result, Kdm4b deficiency attenuated clonogenic potential mediated by AML1-ETO and delayed leukemia progression in vivo . Thus, our results highlight a tumor-promoting role of KDM4B in AML associated with t(8;21). Competing Interests: The authors declare no competing financial interests. (©2021 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.) |
Databáze: | MEDLINE |
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