Abstract
BackgroundA 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.MethodsFirst, 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.ResultsWe 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.ConclusionOur 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.
Highlights
A hallmark of acute promyelocytic leukemia (APL) is the expression of promyelocytic leukemia protein (PML)/RARα fusion protein
We demonstrate that knocking down histone lysine-specific demethylase 3B (KDM3B) leads to an increase in H3K9me1 levels and enhanced chromatin accessibility in transcription start site (TSS) regions of the global genome, which includes the PML/RARα target genes, whereas the levels of modified H3K9me2 are reduced in these regions
With the use of a series of experimental assays and using leukemia cell lines (NB4 and PR9), we proved that KDM3B inhibits the survival of APL NB4 cells and it is required for the differentiation of leukemia cells after all-trans retinoic acid (ATRA) treatment
Summary
A hallmark of acute promyelocytic leukemia (APL) is the expression of PML/RARα fusion protein. 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. The epigenetic information encoded in chromatin is crucial for cell fate and differentiation [1,2,3]. Post-translational modifications in the histone tail are important epigenetic marks linked to transcriptional activation or repression of their specific target genes [4, 5]. Histone lysine methylation is linked to chromatin remodeling and its activity depends on the specific lysine targeted [7, 8]. The methylation of histone H3 lysine 9 (H3K9) is one of the most intensively studied histone modifications because it is considered an epigenetic marker of transcriptionally silenced heterochromatin [4, 9, 10]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call