KDM4B promotes acute myeloid leukemia associated with AML1‐ETO by regulating chromatin accessibility

Ueda, Takeshi; Kanai, Akinori; Komuro, Akiyoshi; Amano, Hideharu; Ota, Kyoko; Honda, Masahiko; Kawazu, Masahito; Okada, Hitoshi

doi:10.1096/fba.2021-00030

Cited by 3 publications

(3 citation statements)

References 54 publications

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“…Accordingly, activation of the β-Catenin pathway was recently demonstrated to be responsible for the preleukaemic to AML transition in distinct preleukaemic diseases due to MDMX overexpression [ 13 ]. In the TgSpi1FA −/− -derived leukaemia cells, the inhibition of WNT/β-catenin signalling did not affect cell proliferation, at least in vitro, consistent with a role of WNT/β-catenin signalling in the preleukaemic to leukaemic transition rather than in leukaemia maintenance.…”

Section: Discussionmentioning

confidence: 99%

FANCA deficiency promotes leukaemic progression by allowing the emergence of cells carrying oncogenic driver mutations

Pawlikowska,

Delestré,

Gregoricchio

et al. 2023

Oncogene

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Leukaemia is caused by the clonal evolution of a cell that accumulates mutations/genomic rearrangements, allowing unrestrained cell growth. However, recent identification of leukaemic mutations in the blood cells of healthy individuals revealed that additional events are required to expand the mutated clones for overt leukaemia. Here, we assessed the functional consequences of deleting the Fanconi anaemia A (Fanca) gene, which encodes a DNA damage response protein, in Spi1 transgenic mice that develop preleukaemic syndrome. FANCA loss increases SPI1-associated disease penetrance and leukaemic progression without increasing the global mutation load of leukaemic clones. However, a high frequency of leukaemic FANCA-depleted cells display heterozygous activating mutations in known oncogenes, such as Kit or Nras, also identified but at low frequency in FANCA-WT mice with preleukaemic syndrome, indicating that FANCA counteracts the emergence of oncogene mutated leukaemic cells. A unique transcriptional signature is associated with the leukaemic status of FANCA-depleted cells, leading to activation of MDM4, NOTCH and Wnt/β-catenin pathways. We show that NOTCH signalling improves the proliferation capacity of FANCA-deficient leukaemic cells. Collectively, our observations indicate that loss of the FANC pathway, known to control genetic instability, fosters the expansion of leukaemic cells carrying oncogenic mutations rather than mutation formation. FANCA loss may contribute to this leukaemogenic progression by reprogramming transcriptomic landscape of the cells.

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Section: Discussionmentioning

confidence: 99%

FANCA deficiency promotes leukaemic progression by allowing the emergence of cells carrying oncogenic driver mutations

Pawlikowska,

Delestré,

Gregoricchio

et al. 2023

Oncogene

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“…The requirement for the binding demethylation of KDM4B with H3K9me3 has been established in the pathogenesis of acute myeloid leukemia (AML) and multiple myeloma (MM), both of which are characterized by non‐solid tumor formation. KDM4B exhibits a defensive mechanism against the induction of cancer cell apoptosis and possesses the ability to facilitate DNA damage responses, consequently enhancing the viability of cancer cells 31 . In addition to its direct involvement in the initiation and progression of cancer cells, KDM4B has the ability to modulate intracellular signaling pathways, consequently exerting an influence on the aberrant proliferation of cancer cells.…”

Section: Kdm4b and Cancermentioning

confidence: 99%

“…KDM4B exhibits a defensive mechanism against the induction of cancer cell apoptosis and possesses the ability to facilitate DNA damage responses, consequently enhancing the viability of cancer cells. 31 In addition to its direct involvement in the initiation and progression of cancer cells, KDM4B has the ability to modulate intracellular signaling pathways, consequently exerting an influence on the aberrant proliferation of cancer cells. In the context of breast cancer cells, the coaction between estrogen receptor α (ERα) and glucocorticoid receptors (GRs) facilitates the upregulation of KDM4B gene expression.…”

Section: Kdm4b and Cancermentioning

confidence: 99%

KDM4B: A promising oncology therapeutic target

Ni,

Tang,

Cheng

et al. 2023

Cancer Science

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Epigenetic modifications are significant in tumor pathogenesis, wherein the process of histone demethylation is indispensable for regulating gene transcription, apoptosis, DNA replication, and repair of damaged DNA. The lysine demethylases (KDMs) serve an essential role in the aforementioned processes, with particular emphasis on the KDM4 family, also referred to as JMJD2. Multiple studies have underscored the significance of the KDM4 family in the regulation of various biological processes including, but not limited to, the cell cycle, DNA repair mechanisms, signaling pathways, and the progression of tumor formation. Nevertheless, it is imperative to elucidate the underlying mechanism of KDM4B, which belongs to the KDM4 gene family. This review presents a comprehensive examination of the structure, mechanism, and function of KDM4B, as well as a critical analysis of the current body of research pertaining to its involvement in tumorigenesis and development. Furthermore, this review explores the potential therapeutic strategies that specifically target KDM4B.

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HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA

Wang

et al. 2023

Leukemia

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KDM4B promotes acute myeloid leukemia associated with AML1‐ETO by regulating chromatin accessibility

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 3 publications

References 54 publications

FANCA deficiency promotes leukaemic progression by allowing the emergence of cells carrying oncogenic driver mutations

FANCA deficiency promotes leukaemic progression by allowing the emergence of cells carrying oncogenic driver mutations

KDM4B: A promising oncology therapeutic target

HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA

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