| 1. |
- Agarwal, Prasoon, et al.
(författare)
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Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:6, s. 6809-6923
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.
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| 2. |
- Alzrigat, Mohammad, et al.
(författare)
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Epigenetics in multiple myeloma : From mechanisms to therapy
- 2018
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Ingår i: Seminars in Cancer Biology. - : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. - 1044-579X .- 1096-3650. ; 51, s. 101-115
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Forskningsöversikt (refereegranskat)abstract
- Multiple myeloma (MM) is a tumor of antibody producing plasmablasts/plasma cells that resides within the bone marrow (BM). In addition to the well-established role of genetic lesions and tumor-microenvironment interactions in the development of MM, deregulated epigenetic mechanisms are emerging as important in MM pathogenesis. Recently, MM sequencing and expression projects have revealed that mutations and copy number variations as well as deregulation in the expression of epigenetic modifiers are characteristic features of MM. In the past decade, several studies have suggested epigenetic mechanisms via DNA methylation, histone modifications and non-coding RNAs as important contributing factors in MM with impacts on disease initiation, progression, clonal heterogeneity and response to treatment. Herein we review the present view and knowledge that has accumulated over the past decades on the role of epigenetics in MM, with focus on the interplay between epigenetic mechanisms and the potential use of epigenetic inhibitors as future treatment modalities for MM.
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| 3. |
- Alzrigat, Mohammad, et al.
(författare)
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EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:6, s. 10213-10224
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Tidskriftsartikel (refereegranskat)abstract
- Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.
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| 4. |
- Alzrigat, Mohammad, et al.
(författare)
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The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:61, s. 103731-103743
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.
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| 5. |
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| 6. |
- Atienza-Párraga, Alba, et al.
(författare)
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Epigenomic re-configuration of primary multiple myeloma underlies the synergistic effect of combined DNMT and EZH2 inhibition.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is characterized by an overexpression of EZH2 and a subsequent increase in H3K27me3-mediated silencing. However, the genome-wide redistribution of this mark in context with other epigenetic tags remains largely unexplored. Here, we show that EZH2 physically interacts with DNMT1 and that combined inhibition leads to a reduced G2/M arrest and increased apoptosis in MM. In addition, we present a catalogue of the genomic regulatory regions in normal plasma cells (NPC) as defined by their individual combination of histone marks. We used ChIP-seq and ATAC-seq data to generate whole-genome NPC chromatin annotations which we further analysed using DNA methylation arrays and RNA-seq. Comparison between NPC and MM demonstrated that, despite the global hypomethylation, enhancers show a tendency towards a higher DNA methylation levels in MM, whereas Polycomb and heterochromatic sites, highly methylated in NPC, show intermediate levels of the mark. Across all examined regulatory regions, 5-azacytidine treatment strongly reduced DNA methylation in MM. Furthermore, we find an extensive re-structuration of the global histone patterns in MM. We noticed a widespread increase in H3K27me3 except at active TSSs/promoters and enhancers, where we found a selective gain of the mark, suggestive of a directed silencing. In contrast, poised TSSs lose H3K27me3 and gain the activation mark H3K27ac, reflecting potential activation. Taken together, we present a comprehensive map of the epigenomic changes in MM as compared to NPC and provide insights into the interplay between EZH2 and DNMT1 in MM.
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| 7. |
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| 8. |
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| 9. |
- Kalushkova, Antonia, et al.
(författare)
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One Omics Approach Does Not Rule Them All : The Metabolome and the Epigenome Join Forces in Haematological Malignancies
- 2021
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Ingår i: EPIGENOMES. - : MDPI. - 2075-4655. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs (miRNAs) play a crucial role in haematological malignancies. These epimutations, with an impact on chromatin accessibility and transcriptional output, are often associated with genomic instability and the emergence of drug resistance, disease progression, and poor survival. In order to exert their functions, epigenetic enzymes utilize cellular metabolites as co-factors and are highly dependent on their availability. By affecting the expression of metabolic enzymes, epigenetic modifiers may aid the generation of metabolite signatures that could be utilized as targets and biomarkers in cancer. This interdependency remains often neglected and poorly represented in studies, despite well-established methods to study the cellular metabolome. This review critically summarizes the current knowledge in the field to provide an integral picture of the interplay between epigenomic alterations and the cellular metabolome in haematological malignancies. Our recent findings defining a distinct metabolic signature upon response to enhancer of zeste homolog 2 (EZH2) inhibition in multiple myeloma (MM) highlight how a shift of preferred metabolic pathways may potentiate novel treatments. The suggested link between the epigenome and the metabolome in haematopoietic tumours holds promise for the use of metabolic signatures as possible biomarkers of response to treatment.
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| 10. |
- Nylund, Patrick, et al.
(författare)
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A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
- 2021
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Ingår i: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.
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