Open AccessKDM4B promotes acute myeloid leukemia associated with AML1‐ETO by regulating chromatin accessibility
Author(s) -
Ueda Takeshi,
Kanai Akinori,
Komuro Akiyoshi,
Amano Hisayuki,
Ota Kazushige,
Honda Masahiko,
Kawazu Masahito,
Okada Hitoshi
Publication year - 2021
Publication title -
faseb bioadvances
Language(s) - English
Resource type - Journals
ISSN - 2573-9832
DOI - 10.1096/fba.2021-00030
Subject(s) - biology , chromatin , demethylase , epigenetics , small hairpin rna , gene silencing , histone , cancer research , myeloid leukemia , gene knockdown , histone h3 , transcription factor , genetics , microbiology and biotechnology , gene
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).