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Overexpression of KDM4D promotes acute myeloid leukemia cell development by activating MCL-1.

ABSTRACT: Acute myeloid leukemia (AML) is regarded as a fatal cancer in the world. The overall survival in adult patients with AML is still poor. As lysine demethylases, the KDM4 family is found highly expressed in many kinds of tumors. In this study, we demonstrate that KDM4D is overexpressed in AML and knockdown of KDM4D not only inhibits the proliferation of AML cells, but also induces cell cycle arrest and apoptosis. Furthermore, our research shows that KDM4D can regulate the expression of MCL-1 by demethylating H3K9me3 at the promoter region in AML cells. Besides, we find that high expression of KDM4D is correlated with poor overall survival in AML patients. Taken together, our study demonstrated that KDM4D can promote MCL-1 expression in AML and may serve as a novel target for the treatment of AML.

SUBMITTER: Wu W

PROVIDER: S-EPMC8129427 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Overexpression of KDM4D promotes acute myeloid leukemia cell development by activating MCL-1.

Wu Wei W Cao Xiaonian X Mo Luxia L

American journal of translational research 20210415 4

Acute myeloid leukemia (AML) is regarded as a fatal cancer in the world. The overall survival in adult patients with AML is still poor. As lysine demethylases, the KDM4 family is found highly expressed in many kinds of tumors. In this study, we demonstrate that KDM4D is overexpressed in AML and knockdown of KDM4D not only inhibits the proliferation of AML cells, but also induces cell cycle arrest and apoptosis. Furthermore, our research shows that KDM4D can regulate the expression of MCL-1 by de ...[more]

PMID: 34017391

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Project description:The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g., S63845, MIK665. However, their effectiveness in acute myeloid leukemia (AML) is limited by compensatory MCL-1 accumulation via the ubiquitin proteasome system. Here, we investigated mechanisms by which kinase inhibitors with Src inhibitory activity e.g., bosutinib (SKI-606) might circumvent this phenomenon. MCL-1 antagonist/SKI-606 co-administration synergistically induced apoptosis in diverse AML cell lines. Consistently, Src or MCL-1 knockdown with shRNA markedly sensitized cells to MCL-1 inhibitors or SKI-606 respectively, while ectopic MCL-1 expression significantly diminished apoptosis. Mechanistically, MCL-1 antagonist exposure induced MCL-1 up-regulation, an event blocked by Src inhibitors or Src shRNA knock-down. MCL-1 down-regulation was associated with diminished transcription and increased K48-linked degradative ubiquitination. Enhanced cell death depended functionally upon down-regulation of phosphorylated STAT3 (Tyr705/Ser727) and cytoprotective downstream targets c-Myc and BCL-xL, as well as BAX/BAK activation, and NOXA induction. Importantly, the Src/MCL-1 inhibitor regimen robustly killed primary AML cells, including primitive progenitors, but spared normal hematopoietic CD34+ cells and human cardiomyocytes. Notably, the regimen significantly improved survival in an MV4-11 cell xenograft model, while reducing tumor burden in two patient-derived xenograft (PDX) AML models and increased survival in a third. These findings argue that Src inhibitors such as SKI-606 potentiate MCL-1 antagonist anti-leukemic activity in vitro and in vivo by blocking MCL-1 antagonist-mediated cytoprotective MCL-1 accumulation by promoting degradative ubiquitination, disrupting STAT-3-mediated transcription, and inducing NOXA-mediated MCL-1 degradation. They also suggest that this strategy may improve MCL-1 antagonist efficacy in AML and potentially other malignancies.

Dataset Information

Overexpression of KDM4D promotes acute myeloid leukemia cell development by activating MCL-1.

Publications

Overexpression of KDM4D promotes acute myeloid leukemia cell development by activating MCL-1.

Similar Datasets

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