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Párraga, Alba Atienza
Publications (5 of 5) Show all publications
Párraga, A. A. (2019). The Epigenome of Multiple Myeloma: From genome-wide analysis to pharmacological manipulation. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>The Epigenome of Multiple Myeloma: From genome-wide analysis to pharmacological manipulation
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nowadays epigenetic dysregulation is known to play a crucial role in virtually all cancers. In multiple myeloma (MM), an extensively heterogeneous malignancy, the key common feature among patients is the gene silencing imposed by the PRC2 complex through the addition of H3K27me3. This thesis focuses on the exploration of the MM epigenomic landscape, with an emphasis on both the interplay between H3K27me3 and other epigenetic tags, and on the effects of a series of inhibitors altering this profile.

In paper I we provide the genome-wide H3K27me3 distribution unique to MM and demonstrate that the silencing of genes in the profile correlates with an advanced and poor-outcome disease. Reduction of H3K27me3 using the EZH2 inhibitor UNC1999 reactivates genes with anti-tumor activity and induces apoptosis in vitro.

EZH2 inhibition also leads to downregulation of the MM oncogenes IRF-4, BLIMP-1, XBP-1 and c-MYC. Paper II identifies miR-125a-3p and miR-320c, predicted to target these oncogenes, as part of the PRC2 targets induced upon treatment.

In addition, H3K27me3 can be recognized and bound by the PRC1 complex. In paper III we show that inhibition of PRC1 using PTC-209 induces apoptosis and this is further enhanced when PTC-209 is combined with UNC1999. Moreover, PTC-209 has been previously shown to reduce the expression of c-MYC. Combined treatment using PTC-209 and JQ1, demonstrated to downregulate c-MYC, results in additive and synergistic effects in reducing MM cell viability.

In paper IV we present the first catalogue of genomic regulatory regions in normal plasma cells, as predicted by their combinations of histone marks. Using this, we demonstrate that in MM a subset of TSSs and enhancers become targeted by H3K27me3 and display high DNA methylation, pointing towards a possible silencing. Conversely, poised TSSs lose H3K27me3 and seemingly become de novo activated. Furthermore, we show that EZH2 physically interacts with the DNA methyltransferase DNMT1 and that combined inhibition using UNC1999 and the DNA hypomethylating agent AZA blocks the G2/M arrest triggered by AZA and induces apoptosis.

In summary, this thesis highlights the complex interconnectivity of epigenetic mechanisms in MM and provides proof-of-principle of the anti-MM effects derived from inhibiting epigenetic components in single or combinatorial regimens.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 58
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1571
Keywords
Multiple myeloma, epigenetics, Polycomb, EZH2, miRNA, DNA methylation, inhibitor.
National Category
Medical Genetics Cancer and Oncology Genetics
Research subject
Experimental Pathology
Identifiers
urn:nbn:se:uu:diva-377438 (URN)978-91-513-0650-6 (ISBN)
Public defence
2019-06-07, Rudbecksalen, Rudbecklaboratoriet - Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-05-16 Created: 2019-04-14 Last updated: 2019-06-18
Alzrigat, M., Párraga, A. A. & Jernberg-Wiklund, H. (2018). Epigenetics in multiple myeloma: From mechanisms to therapy. Seminars in Cancer Biology, 51, 101-115
Open this publication in new window or tab >>Epigenetics in multiple myeloma: From mechanisms to therapy
2018 (English)In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 51, p. 101-115Article, review/survey (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2018
Keywords
Multiple myeloma, Epigenetics, Epigenetic therapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-363884 (URN)10.1016/j.semcancer.2017.09.007 (DOI)000442066000011 ()28962927 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Alzrigat, M., Párraga, A. A., Agarwal, P., Zureigat, H., Österborg, A., Nahi, H., . . . Jernberg Wiklund, H. (2017). EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.. OncoTarget, 8(6), 10213-10224
Open this publication in new window or tab >>EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, p. 10213-10224Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-312396 (URN)10.18632/oncotarget.14378 (DOI)000394181800106 ()28052011 (PubMedID)
Available from: 2017-01-09 Created: 2017-01-09 Last updated: 2019-04-14Bibliographically approved
Alzrigat, M., Párraga, A. A., Majumder, M., Ma, A., Jin, J., Nilsson, K., . . . Jernberg Wiklund, H. (2017). 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. OncoTarget, 8(61), 103731-103743
Open this publication in new window or tab >>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
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103731-103743Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Multiple Myeloma, Epigenetics, Polycomb, BMI-1, PTC-209
National Category
Cancer and Oncology
Research subject
Medical Science; Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-313562 (URN)10.18632/oncotarget.21909 (DOI)000419562500079 ()29262596 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2017-01-20 Created: 2017-01-20 Last updated: 2019-04-14Bibliographically approved
Agarwal, P., Alzrigat, M., Párraga, A. A., Enroth, S., Singh, U., Ungerstedt, J., . . . Jernberg-Wiklund, H. (2016). 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.. OncoTarget, 7(6), 6809-6923
Open this publication in new window or tab >>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.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 6, p. 6809-6923Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
multiple myeloma; Polycomb; EZH2; H3K27me3; UNC1999
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-289186 (URN)10.18632/oncotarget.6843 (DOI)000376123100032 ()26755663 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilNIH (National Institute of Health), R01GM103893
Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2019-04-14Bibliographically approved
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