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Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Acute Myeloid Leukemia | Primary research

KDM3B suppresses APL progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα

Authors: Xinrui Wang, Huiyong Fan, Congling Xu, Guojuan Jiang, Haiwei Wang, Ji Zhang

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

A hallmark of acute promyelocytic leukemia (APL) is the expression of PML/RARα fusion protein. Treatment with all-trans retinoic acid (ATRA) results in the terminal differentiation of neutrophil granulocytes. However, the underlying mechanisms remain largely unknown. Here, we identify and elucidate a novel differentiation-suppressive model of APL involving the histone demethylase KDM3B, which has been identified as a suppressor of the tumor genes involved in hematopoietic malignancies.

Methods

First, we established a KDM3B knockdown NB4 cell model to determine the functional characteristics of KDM3B by cell proliferation assay and flow cytometry. Then, we performed ChIP-seq and ATAC-seq to search for potential relationships among KDM3B, histone modification (H3K9me1/me2) and the chromatin state. Finally, molecular biological techniques and a multi-omics analysis were used to explore the role of KDM3B in differentiation of the leukemia cells after ATRA treatment.

Results

We found that knocking down KDM3B contributed to the growth of NB4 APL cells via the promotion of cell-cycle progression and blocked granulocytic differentiation. Through global and molecular approaches, we provided futher evidence that knocking down KDM3B altered the global distribution of H3K9me1/me2 and increased the chromatin accessibility. Moreover, knocking down KDM3B inhibited the ATRA-induced degradation of the PML/RARα oncoprotein.

Conclusion

Our study suggested that KDM3B was able to inhibit APL progression by maintaining chromatin in a compact state and facilitating the ATRA-mediated degradation of PML/RARα. Taken together, the results show that KDM3B may be an alternative target for the treatment regimens and the targeted therapy for APL by sustaining the function of PML/RARα fusion protein.
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Metadata
Title
KDM3B suppresses APL progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα
Authors
Xinrui Wang
Huiyong Fan
Congling Xu
Guojuan Jiang
Haiwei Wang
Ji Zhang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0979-7

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