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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137105 | GEO | 2020/04/10

REPOSITORIES: GEO

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

Project description:Background:A hallmark of acute promyelocytic leukemia (APL) is the expression of PML/RAR? 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/RAR? 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/RAR?. 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/RAR? fusion protein.

| S-EPMC6778369 | biostudies-literature

KDM3B suppresses APL Progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα (RNA-seq data set)

Project description:Histone demethylase KDM3B is considered to play a critical role in leukemogenesis. To the best of our knowledge, this study is the first attempt to probe the detailed genetic and epigenetic mechanisms underlying the regulation of KDM3B in the development of APL from the perspectives of multi-layer omics. Results of the present study demonstrate that KDM3B exerts anti-APL effect by directly modulating H3K9me1/me2 levels to maintain compact chromatin status, but also indicate the interaction between KDM3B and PML/RARα regulates degradation of PML/RARα.

2020-04-10 | GSE137104 | GEO

KDM3B suppresses APL Progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα (ChIP-seq data set)

2020-04-10 | GSE137103 | GEO

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

Project description:KDM3B suppresses APL Progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα

| PRJNA564552 | ENA

KDM3B suppresses APL Progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα (ChIP-seq data set)

Project description:KDM3B suppresses APL Progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα (ChIP-seq data set)

| PRJNA564558 | ENA

KDM3B suppresses APL Progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα (RNA-seq data set)

Project description:KDM3B suppresses APL Progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARα (RNA-seq data set)

| PRJNA564557 | ENA

USP22 regulates APL differentiation via PML-RARα stabilization and IFN repression.

Project description:Ubiquitin-specific peptidase 22 (USP22) is a deubiquitinating enzyme (DUB) that underlies tumorigenicity, proliferation, cell death and differentiation through deubiquitination of histone and non-histone targets. Ubiquitination determines stability, localization and functions of cell fate proteins and controls cell-protective signaling pathways to surveil cell cycle progression. In a variety of carcinomas, lymphomas and leukemias, ubiquitination regulates the tumor-suppressive functions of the promyelocytic leukemia protein (PML), but PML-specific DUBs, DUB-controlled PML ubiquitin sites and the functional consequences of PML (de)ubiquitination remain unclear. Here, we identify USP22 as regulator of PML and the oncogenic acute promyelocytic leukemia (APL) fusion PML-RARα protein stability and identify a destabilizing role of PML residue K394. Additionally, loss of USP22 upregulates interferon (IFN) and IFN-stimulated gene (ISG) expression in APL and induces PML-RARα stabilization and a potentiation of the cell-autonomous sensitivity towards all-trans retinoic acid (ATRA)-mediated differentiation. Our findings imply USP22-dependent surveillance of PML-RARα stability and IFN signaling as important regulator of APL pathogenesis, with implications for viral mimicry, differentiation and cell fate regulation in other leukemia subtypes.

| S-EPMC10928094 | biostudies-literature

RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner.

Project description:The major oncogenic driver of acute promyelocytic leukemia (APL) is the fusion protein PML-RARα originated from the chromosomal translocation t(15;17). All-trans retinoic acid (ATRA) and arsenic trioxide cure most patients by directly targeting PML-RARα. However, major issues including the resistance of ATRA and arsenic therapy still remain in APL clinical management. Here we showed that compound Z-10, a nitro-ligand of retinoid X receptor α (RXRα), strongly promoted the cAMP-independent apoptosis of both ATRA- sensitive and resistant NB4 cells via the induction of caspase-mediated PML-RARα degradation. RXRα was vital for the stability of both PML-RARα and RARα likely through the interactions. The binding of Z-10 to RXRα dramatically inhibited the interaction of RXRα with PML-RARα but not with RARα, leading to Z-10's selective induction of PML-RARα but not RARα degradation. Z-36 and Z-38, two derivatives of Z-10, had improved potency of inducing PML-RARα reduction and NB4 cell apoptosis. Hence, RXRα ligand Z-10 and its derivatives could target both ATRA- sensitive and resistant APL cells through their distinct acting mechanism, and are potential drug leads for APL treatment.

| S-EPMC5355346 | biostudies-literature

KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2

Project description:Epigenetic abnormalities are frequently involved in the initiation and progression of cancers including acute myeloid leukemia (AML). A subtype of AML, Acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of PML-RARα. PML-RARα was reported as a transcription repressor through the interaction with NCoR/HDAC complexes leading to the mis-suppression of its target genes and differentiation blockage. While previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDM5A is a demethylase of histone H3 lysine 4 di- and tri- methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, we detected KDM5A binding in 1,889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARα target genes primarily by controlling the H3K4me2 in the promoters and 5’ end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455 on its own could phenocopy the differentiation effects as KDM5A loss in NB4 cells. CPI-455 treatment or KDM5A knockout could greatly sensitize NB4 cells to ATRA induced differentiation. Our findings indicated that KDM5A contributed to the differentiation blockage in the APL cell line NB4, and inhibition of KDM5A could greatly potentiate NB4 differentiation.

2021-04-01 | GSE152397 | GEO

Adefovir dipivoxil inhibits APL progression through degradation of the oncoprotein PML-RARA

Project description:Acute promyelocytic leukemia (APL) is highly aggressive and is frequently associated with disseminated intravascular coagulation and high early death rates. Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with APL, there are limited treatments for APL patients with RA resistance. Here we report an atypical APL patient, with an APL-like disease that developed very slowly without anti-leukemia therapy for nearly 2 years. During that time, the patient only intermittently received anti-HBV drugs, i.e., the combination of adefovir dipivoxil (ADV) and entecavir (ETV), leading us to hypothesize that ADV and/or ETV could inhibit APL progression. Our results showed that anti-HBV drugs ADV and ETV both exhibited significantly inhibitory effects on APL cells, and ADV indicated a much greater cytotoxic effect than ETV on APL cells. We further found that ADV significantly promoted APL cell differentiation and apoptosis, thereby restraining the progression of APL. Most importantly, our study uncovered a novel mechanism of ADV prohibiting APL progression, which was mediated, at least in part, by inhibition of TRIB3 and degradation of the oncoprotein PML-RARA, therefore leading to APL cell differentiation and apoptosis. Taken together, our study demonstrated that ADV, an anti-HBV drug, had significantly inhibitory effects on APL, and provided a novel therapeutic strategy for APL patients with RA resistance. Supplementary Information The online version contains supplementary material available at 10.1186/s40164-022-00355-1.

| S-EPMC9676767 | biostudies-literature

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