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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Multiple Myeloma | Review

Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer

Authors: Hussein Ghamlouch, Eileen M. Boyle, Patrick Blaney, Yubao Wang, Jinyoung Choi, Louis Williams, Michael Bauer, Daniel Auclair, Benedetto Bruno, Brian A. Walker, Faith E. Davies, Gareth J. Morgan

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Despite  improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.
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Literature
1.
Pawlyn C, Bright MD, Buros AF, Stein CK, Walters Z, Aronson LI, et al. Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer J. 2017;7(3):e549.PubMedPubMedCentralCrossRef
2.
Rajkumar SV. Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management. Am J Hematol. 2018;93(8):981–1114.PubMedCentralCrossRef
3.
Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113(22):5412–7.PubMedPubMedCentralCrossRef
4.
Walker BA, Wardell CP, Chiecchio L, Smith EM, Boyd KD, Neri A, et al. Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma. Blood. 2011;117(2):553–62.PubMedCrossRef
5.
Pawlyn C, Kaiser MF, Davies FE, Morgan GJ. Current and potential epigenetic targets in multiple myeloma. Epigenomics. 2014;6(2):215–28.PubMedCrossRef
6.
7.
van Mierlo G, Veenstra GJC, Vermeulen M, Marks H. The complexity of PRC2 subcomplexes. Trends Cell Biol. 2019;29(8):660–71.PubMedCrossRef
8.
Morgan MAJ, Shilatifard A. Reevaluating the roles of histone-modifying enzymes and their associated chromatin modifications in transcriptional regulation. Nat Genet. 2020;52(12):1271–81.PubMedCrossRef
9.
10.
Radulovic V, de Haan G, Klauke K. Polycomb-group proteins in hematopoietic stem cell regulation and hematopoietic neoplasms. Leukemia. 2013;27(3):523–33.PubMedCrossRef
11.
Varlet E, Ovejero S, Martinez AM, Cavalli G, Moreaux J. Role of polycomb complexes in normal and malignant plasma cells. Int J Mol Sci. 2020;21(21).
12.
Agarwal P, Alzrigat M, Parraga AA, Enroth S, Singh U, Ungerstedt J, et al. 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. 2016;7(6):6809–23.PubMedPubMedCentralCrossRef
13.
Lavarone E, Barbieri CM, Pasini D. Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity. Nat Commun. 2019;10(1):1679.PubMedPubMedCentralCrossRef
14.
Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL, et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell. 2008;32(4):503–18.PubMedPubMedCentralCrossRef
15.
Mason MJ, Schinke C, Eng CLP, Towfic F, Gruber F, Dervan A, et al. Multiple myeloma DREAM challenge reveals epigenetic regulator PHF19 as marker of aggressive disease. Leukemia. 2020;34(7):1866–74.PubMedPubMedCentralCrossRef
16.
Schinke CD, Bird JT, Qu P, Yaccoby S, Lyzogubov VV, Shelton R, et al. PHF19 inhibition as a therapeutic target in multiple myeloma. Curr Res Transl Med. 2021;69(3):103290.PubMedCrossRef
17.
Lonie A, D'Andrea R, Paro R, Saint R. Molecular characterisation of the Polycomblike gene of Drosophila melanogaster, a trans-acting negative regulator of homeotic gene expression. Development. 1994;120(9):2629–36.PubMedCrossRef
18.
Cao R, Wang H, He J, Erdjument-Bromage H, Tempst P, Zhang Y. Role of hPHF1 in H3K27 methylation and Hox gene silencing. Mol Cell Biol. 2008;28(5):1862–72.PubMedCrossRef
19.
Casanova M, Preissner T, Cerase A, Poot R, Yamada D, Li X, et al. Polycomblike 2 facilitates the recruitment of PRC2 polycomb group complexes to the inactive X chromosome and to target loci in embryonic stem cells. Development. 2011;138(8):1471–82.PubMedPubMedCentralCrossRef
20.
Ballare C, Lange M, Lapinaite A, Martin GM, Morey L, Pascual G, et al. Phf19 links methylated Lys36 of histone H3 to regulation of polycomb activity. Nat Struct Mol Biol. 2012;19(12):1257–65.PubMedPubMedCentralCrossRef
21.
Hunkapiller J, Shen Y, Diaz A, Cagney G, McCleary D, Ramalho-Santos M, et al. Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal. PLoS Genet. 2012;8(3):e1002576.PubMedPubMedCentralCrossRef
22.
Wang S, Robertson GP, Zhu J. A novel human homologue of Drosophila polycomblike gene is up-regulated in multiple cancers. Gene. 2004;343(1):69–78.PubMedCrossRef
23.
Zheng R, Wan C, Mei S, Qin Q, Wu Q, Sun H, et al. Cistrome data browser: expanded datasets and new tools for gene regulatory analysis. Nucleic Acids Res. 2019;47(D1):D729–D35.PubMedCrossRef
24.
Mei S, Qin Q, Wu Q, Sun H, Zheng R, Zang C, et al. Cistrome data browser: a data portal for ChIP-Seq and chromatin accessibility data in human and mouse. Nucleic Acids Res. 2017;45(D1):D658–D62.PubMedCrossRef
25.
Loughran G, Jungreis I, Tzani I, Power M, Dmitriev RI, Ivanov IP, et al. Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response. J Biol Chem. 2018;293(12):4434–44.PubMedPubMedCentralCrossRef
26.
Boulay G, Rosnoblet C, Guerardel C, Angrand PO, Leprince D. Functional characterization of human Polycomb-like 3 isoforms identifies them as components of distinct EZH2 protein complexes. Biochem J. 2011;434(2):333–42.PubMedCrossRef
27.
Li H, Liefke R, Jiang J, Kurland JV, Tian W, Deng P, et al. Polycomb-like proteins link the PRC2 complex to CpG islands. Nature. 2017;549(7671):287–91.PubMedPubMedCentralCrossRef
28.
29.
Brien GL, Gambero G, O'Connell DJ, Jerman E, Turner SA, Egan CM, et al. Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation. Nat Struct Mol Biol. 2012;19(12):1273–81.PubMedCrossRef
30.
Cai Z, Qian ZY, Jiang H, Ma N, Li Z, Liu LY, et al. hPCL3s promotes hepatocellular carcinoma metastasis by activating beta-catenin signaling. Cancer Res. 2018;78(10):2536–49.PubMedCrossRef
31.
Schmitges FW, Prusty AB, Faty M, Stutzer A, Lingaraju GM, Aiwazian J, et al. Histone methylation by PRC2 is inhibited by active chromatin marks. Mol Cell. 2011;42(3):330–41.PubMedCrossRef
32.
Dong C, Nakagawa R, Oyama K, Yamamoto Y, Zhang W, Dong A, et al. Structural basis for histone variant H3tK27me3 recognition by PHF1 and PHF19. Elife. 2020;9.
33.
Kloet SL, Makowski MM, Baymaz HI, van Voorthuijsen L, Karemaker ID, Santanach A, et al. The dynamic interactome and genomic targets of Polycomb complexes during stem-cell differentiation. Nat Struct Mol Biol. 2016;23(7):682–90.PubMedPubMedCentralCrossRef
34.
Ji Y, Fioravanti J, Zhu W, Wang H, Wu T, Hu J, et al. miR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8(+) T cell fate. Nat Commun. 2019;10(1):2157.PubMedPubMedCentralCrossRef
35.
Jain P, Ballare C, Blanco E, Vizan P, Di Croce L. PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells. Elife. 2020;9.
36.
Deng Q, Hou J, Feng L, Lv A, Ke X, Liang H, et al. PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/beta-catenin axis. Cell Death Dis. 2018;9(11):1049.PubMedPubMedCentralCrossRef
37.
Li G, Warden C, Zou Z, Neman J, Krueger JS, Jain A, et al. Altered expression of polycomb group genes in glioblastoma multiforme. PLoS One. 2013;8(11):e80970.PubMedPubMedCentralCrossRef
38.
Chen S, Fu Z, Wen S, Yang X, Yu C, Zhou W, et al. Expression and diagnostic value of miR-497 and miR-1246 in hepatocellular carcinoma. Front Genet. 2021;12:666306.PubMedPubMedCentralCrossRef
39.
Xu H, Hu YW, Zhao JY, Hu XM, Li SF, Wang YC, et al. MicroRNA-195-5p acts as an anti-oncogene by targeting PHF19 in hepatocellular carcinoma. Oncol Rep. 2015;34(1):175–82.PubMedCrossRef
40.
Xiaoyun S, Yuyuan Z, Jie X, Yingjie N, Qing X, Yuezhen D, et al. PHF19 activates hedgehog signaling and promotes tumorigenesis in hepatocellular carcinoma. Exp Cell Res. 2021;406(1):112690.PubMedCrossRef
41.
Ruan S, Zhang H, Tian X, Zhang Z, Huang H, Shi C, et al. PHD finger protein 19 enhances the resistance of ovarian cancer cells to compound fuling granule by protecting cell growth, invasion, migration, and stemness. Front Pharmacol. 2020;11:150.PubMedPubMedCentralCrossRef
42.
Tao F, Tian X, Ruan S, Shen M, Zhang Z. miR-211 sponges lncRNA MALAT1 to suppress tumor growth and progression through inhibiting PHF19 in ovarian carcinoma. FASEB J. 2018:fj201800495RR.
43.
Ghislin S, Deshayes F, Middendorp S, Boggetto N, Alcaide-Loridan C. PHF19 and Akt control the switch between proliferative and invasive states in melanoma. Cell Cycle. 2012;11(8):1634–45.PubMedCrossRef
44.
Murakami H, Ito S, Tanaka H, Kondo E, Kodera Y, Nakanishi H. Establishment of new intraperitoneal paclitaxel-resistant gastric cancer cell lines and comprehensive gene expression analysis. Anticancer Res. 2013;33(10):4299–307.PubMed
45.
Wang H, Xu P, Sun G, Lv J, Cao J, Xu Z. Downregulation of PHF19 inhibits cell growth and migration in gastric cancer. Scand J Gastroenterol. 2020;55(6):687–93.PubMedCrossRef
46.
Zhang J, Lv W, Liu Y, Fu W, Chen B, Ma Q, et al. LINC_00355 promotes gastric cancer progression by upregulating PHF19 expression through sponging miR-15a-5p. BMC Cancer. 2021;21(1):657.PubMedPubMedCentralCrossRef
47.
Gollavilli PN, Pawar A, Wilder-Romans K, Natesan R, Engelke CG, Dommeti VL, et al. EWS/ETS-driven ewing sarcoma requires BET bromodomain proteins. Cancer Res. 2018;78(16):4760–73.PubMedCrossRef
48.
Li P, Sun J, Ruan Y, Song L. High PHD Finger Protein 19 (PHF19) expression predicts poor prognosis in colorectal cancer: a retrospective study. PeerJ. 2021;9:e11551.PubMedPubMedCentralCrossRef
49.
Abdelfettah S, Boulay G, Dubuissez M, Spruyt N, Garcia SP, Rengarajan S, et al. hPCL3S promotes proliferation and migration of androgen-independent prostate cancer cells. Oncotarget. 2020;11(12):1051–74.PubMedPubMedCentralCrossRef
50.
Garcia-Montolio M, Ballare C, Blanco E, Gutierrez A, Aranda S, Gomez A, et al. Polycomb factor PHF19 controls cell growth and differentiation toward erythroid pathway in chronic myeloid leukemia cells. Front Cell Dev Biol. 2021;9:655201.PubMedPubMedCentralCrossRef
51.
52.
Yu T, Du C, Ma X, Sui W, Yu Z, Liu L, et al. Polycomb-like protein 3 induces proliferation and drug resistance in multiple myeloma and is regulated by miRNA-15a. Mol Cancer Res. 2020;18(7):1063–73.PubMedCrossRef
53.
Li Z, Liu L, Du C, Yu Z, Yang Y, Xu J, et al. Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma. Cancer Gene Ther. 2020;27(12):869–77.PubMedCrossRef
54.
Bagger FO, Kinalis S, Rapin N. BloodSpot: a database of healthy and malignant haematopoiesis updated with purified and single cell mRNA sequencing profiles. Nucleic Acids Res. 2019;47(D1):D881–D5.PubMedCrossRef
55.
Kassambara A, Reme T, Jourdan M, Fest T, Hose D, Tarte K, et al. GenomicScape: an easy-to-use web tool for gene expression data analysis. Application to investigate the molecular events in the differentiation of B cells into plasma cells. PLoS Comput Biol. 2015;11(1):e1004077.PubMedPubMedCentralCrossRef
56.
Vizan P, Gutierrez A, Espejo I, Garcia-Montolio M, Lange M, Carretero A, et al. The Polycomb-associated factor PHF19 controls hematopoietic stem cell state and differentiation. Sci Adv. 2020;6(32):eabb2745.PubMedPubMedCentralCrossRef
57.
Majewski IJ, Ritchie ME, Phipson B, Corbin J, Pakusch M, Ebert A, et al. Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood. 2010;116(5):731–9.PubMedCrossRef
58.
Lee SC, Miller S, Hyland C, Kauppi M, Lebois M, Di Rago L, et al. Polycomb repressive complex 2 component Suz12 is required for hematopoietic stem cell function and lymphopoiesis. Blood. 2015;126(2):167–75.PubMedCrossRef
59.
Yu W, Zhang F, Wang S, Fu Y, Chen J, Liang X, et al. Depletion of polycomb repressive complex 2 core component EED impairs fetal hematopoiesis. Cell Death Dis. 2017;8(4):e2744.PubMedPubMedCentralCrossRef
60.
Kinkel SA, Galeev R, Flensburg C, Keniry A, Breslin K, Gilan O, et al. Jarid2 regulates hematopoietic stem cell function by acting with polycomb repressive complex 2. Blood. 2015;125(12):1890–900.PubMedPubMedCentralCrossRef
61.
Rothberg JLM, Maganti HB, Jrade H, Porter CJ, Palidwor GA, Cafariello C, et al. Mtf2-PRC2 control of canonical Wnt signaling is required for definitive erythropoiesis. Cell Discov. 2018;4:21.PubMedPubMedCentralCrossRef
62.
Beguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013;23(5):677–92.PubMedPubMedCentralCrossRef
63.
Guo M, Price MJ, Patterson DG, Barwick BG, Haines RR, Kania AK, et al. EZH2 represses the B cell transcriptional program and regulates antibody-secreting cell metabolism and antibody production. J Immunol. 2018;200(3):1039–52.PubMedCrossRef
64.
Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest. 2013;123(12):5009–22.PubMedPubMedCentralCrossRef
65.
Beguelin W, Teater M, Gearhart MD, Calvo Fernandez MT, Goldstein RL, Cardenas MG, et al. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis. Cancer Cell. 2016;30(2):197–213.PubMedPubMedCentralCrossRef
66.
Beguelin W, Rivas MA, Calvo Fernandez MT, Teater M, Purwada A, Redmond D, et al. EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop. Nat Commun. 2017;8(1):877.PubMedPubMedCentralCrossRef
67.
Jego G, Bataille R, Pellat-Deceunynck C. Interleukin-6 is a growth factor for nonmalignant human plasmablasts. Blood. 2001;97(6):1817–22.PubMedCrossRef
68.
Jourdan M, Caraux A, Caron G, Robert N, Fiol G, Reme T, et al. Characterization of a transitional preplasmablast population in the process of human B cell to plasma cell differentiation. J Immunol. 2011;187(8):3931–41.PubMedCrossRef
69.
Jourdan M, Caraux A, De Vos J, Fiol G, Larroque M, Cognot C, et al. An in vitro model of differentiation of memory B cells into plasmablasts and plasma cells including detailed phenotypic and molecular characterization. Blood. 2009;114(25):5173–81.PubMedCrossRef
70.
Herviou L, Jourdan M, Martinez AM, Cavalli G, Moreaux J. EZH2 is overexpressed in transitional preplasmablasts and is involved in human plasma cell differentiation. Leukemia. 2019;33(8):2047–60.PubMedPubMedCentralCrossRef
71.
Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338(6113):1465–9.PubMedPubMedCentralCrossRef
72.
Xu H, Xu K, He HH, Zang C, Chen CH, Chen Y, et al. Integrative analysis reveals the transcriptional collaboration between EZH2 and E2F1 in the regulation of cancer-related gene expression. Mol Cancer Res. 2016;14(2):163–72.PubMedCrossRef
73.
Musselman CA, Avvakumov N, Watanabe R, Abraham CG, Lalonde ME, Hong Z, et al. Molecular basis for H3K36me3 recognition by the tudor domain of PHF1. Nat Struct Mol Biol. 2012;19(12):1266–72.PubMedPubMedCentralCrossRef
74.
Li X, Isono K, Yamada D, Endo TA, Endoh M, Shinga J, et al. Mammalian polycomb-like Pcl2/Mtf2 is a novel regulatory component of PRC2 that can differentially modulate polycomb activity both at the Hox gene cluster and at Cdkn2a genes. Mol Cell Biol. 2011;31(2):351–64.PubMedCrossRef
75.
Walker E, Chang WY, Hunkapiller J, Cagney G, Garcha K, Torchia J, et al. Polycomb-like 2 associates with PRC2 and regulates transcriptional networks during mouse embryonic stem cell self-renewal and differentiation. Cell Stem Cell. 2010;6(2):153–66.PubMedPubMedCentralCrossRef
76.
Ning F, Wang C, Niu S, Xu H, Xia K, Wang N. Transcription factor Phf19 positively regulates germinal center reactions that underlies its role in rheumatoid arthritis. Am J Transl Res. 2018;10(1):200–11.PubMedPubMedCentral
77.
Buil A, Martinez-Perez A, Perera-Lluna A, Rib L, Caminal P, Soria JM. A new gene-based association test for genome-wide association studies. BMC Proc. 2009;3(Suppl 7):S130.PubMedPubMedCentralCrossRef
78.
Chang M, Rowland CM, Garcia VE, Schrodi SJ, Catanese JJ, van der Helm-van Mil AH, et al. A large-scale rheumatoid arthritis genetic study identifies association at chromosome 9q33.2. PLoS Genet. 2008;4(6):e1000107.PubMedPubMedCentralCrossRef
79.
Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood. 2002;99(5):1745–57.PubMedCrossRef
80.
Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J Jr. Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development. Blood. 2003;101(3):1128–40.PubMedCrossRef
81.
Pawlyn C, Kaiser MF, Heuck C, Melchor L, Wardell CP, Murison A, et al. The spectrum and clinical impact of epigenetic modifier mutations in myeloma. Clin Cancer Res. 2016;22(23):5783–94.PubMedPubMedCentralCrossRef
82.
Erokhin M, Chetverina O, Gyorffy B, Tatarskiy VV, Mogila V, Shtil AA, et al. Clinical correlations of polycomb repressive complex 2 in different tumor types. Cancers. 2021;13(13).
83.
Herviou L, Kassambara A, Boireau S, Robert N, Requirand G, Muller-Tidow C, et al. PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs. Clin Epigenetics. 2018;10(1):121.PubMedPubMedCentralCrossRef
84.
Boyle EM, Rosenthal A, Ghamlouch H, Wang Y, Farmer P, Rutherford M, et al. Plasma cells expression from smouldering myeloma to myeloma reveals the importance of the PRC2 complex, cell cycle progression, and the divergent evolutionary pathways within the different molecular subgroups. Leukemia. 2021.
85.
Neo WH, Lim JF, Grumont R, Gerondakis S, Su IH. c-Rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells. J Biol Chem. 2014;289(46):31693–707.PubMedPubMedCentralCrossRef
86.
Rizk M, Rizq O, Oshima M, Nakajima-Takagi Y, Koide S, Saraya A, et al. Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma. Cancer Sci. 2019;110(12):3695–707.PubMedPubMedCentralCrossRef
87.
Croonquist PA, Van Ness B. The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype. Oncogene. 2005;24(41):6269–80.PubMedCrossRef
88.
Pan YM, Wang CG, Zhu M, Xing R, Cui JT, Li WM, et al. STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer. Mol Cancer. 2016;15(1):79.PubMedPubMedCentralCrossRef
89.
Rizq O, Mimura N, Oshima M, Saraya A, Koide S, Kato Y, et al. Dual Inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition. Clin Cancer Res. 2017;23(16):4817–30.PubMedPubMedCentralCrossRef
90.
Gonzalez ME, DuPrie ML, Krueger H, Merajver SD, Ventura AC, Toy KA, et al. Histone methyltransferase EZH2 induces Akt-dependent genomic instability and BRCA1 inhibition in breast cancer. Cancer Res. 2011;71(6):2360–70.PubMedPubMedCentralCrossRef
91.
Kim J, Lee Y, Lu X, Song B, Fong KW, Cao Q, et al. Polycomb- and methylation-independent roles of EZH2 as a transcription activator. Cell Rep. 2018;25(10):2808–20 e4.PubMedPubMedCentralCrossRef
92.
Yan J, Li B, Lin B, Lee PT, Chung TH, Tan J, et al. EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma. Blood. 2016;128(7):948–58.PubMedCrossRef
93.
94.
Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, et al. Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science. 2005;310(5746):306–10.PubMedCrossRef
95.
Kikuchi J, Koyama D, Wada T, Izumi T, Hofgaard PO, Bogen B, et al. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma. J Clin Invest. 2015;125(12):4375–90.PubMedPubMedCentralCrossRef
96.
Kalushkova A, Fryknas M, Lemaire M, Fristedt C, Agarwal P, Eriksson M, et al. Polycomb target genes are silenced in multiple myeloma. PLoS One. 2010;5(7):e11483.PubMedPubMedCentralCrossRef
97.
Popovic R, Martinez-Garcia E, Giannopoulou EG, Zhang Q, Zhang Q, Ezponda T, et al. Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation. PLoS Genet. 2014;10(9):e1004566.PubMedPubMedCentralCrossRef
98.
Alzrigat M, Jernberg-Wiklund H, Licht JD. Targeting EZH2 in multiple myeloma-multifaceted anti-tumor activity. Epigenomes. 2018;2(3).
99.
Nylund P, Atienza Parraga A, Haglof J, De Bruyne E, Menu E, Garrido-Zabala B, et al. A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma. Cell Death Dis. 2021;12(2):167.PubMedPubMedCentralCrossRef
100.
101.
Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007;449(7163):731–4.PubMedCrossRef
102.
Ezponda T, Dupere-Richer D, Will CM, Small EC, Varghese N, Patel T, et al. UTX/KDM6A loss enhances the malignant phenotype of multiple myeloma and sensitizes Cells to EZH2 inhibition. Cell Rep. 2017;21(3):628–40.PubMedPubMedCentralCrossRef
103.
Ren Z, Ahn JH, Liu H, Tsai YH, Bhanu NV, Koss B, et al. PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation. Blood. 2019;134(14):1176–89.PubMedPubMedCentralCrossRef
104.
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483(7391):603–7.PubMedPubMedCentralCrossRef
105.
Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320–34.PubMedPubMedCentralCrossRef
106.
Fedele PL, Liao Y, Gong JN, Yao Y, van Delft MF, Low MSY, et al. The transcription factor IRF4 represses proapoptotic BMF and BIM to licence multiple myeloma survival. Leukemia. 2021;35(7):2114–8.PubMedCrossRef
107.
Rhyasen GW, Hattersley MM, Yao Y, Dulak A, Wang W, Petteruti P, et al. AZD5153: a novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies. Mol Cancer Ther. 2016;15(11):2563–74.PubMedCrossRef
108.
Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012;151(1):56–67.PubMedPubMedCentralCrossRef
109.
110.
Ohguchi H, Park PMC, Wang T, Gryder BE, Ogiya D, Kurata K, et al. Lysine demethylase 5A is required for MYC driven transcription in multiple myeloma. Blood Cancer Discov. 2021;2(4):370–87.PubMedPubMedCentralCrossRef
111.
Shaughnessy JD Jr, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109(6):2276–84.PubMedCrossRef
112.
Kuiper R, Broyl A, de Knegt Y, van Vliet MH, van Beers EH, van der Holt B, et al. A gene expression signature for high-risk multiple myeloma. Leukemia. 2012;26(11):2406–13.PubMedCrossRef
113.
Decaux O, Lode L, Magrangeas F, Charbonnel C, Gouraud W, Jezequel P, et al. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome. J Clin Oncol. 2008;26(29):4798–805.PubMedCrossRef
114.
Wall MA, Turkarslan S, Wu WJ, Danziger SA, Reiss DJ, Mason MJ, et al. Genetic program activity delineates risk, relapse, and therapy responsiveness in multiple myeloma. NPJ Precis Oncol. 2021;5(1):60.PubMedPubMedCentralCrossRef
115.
Johnson T, Yu C, Huang Z, Xu S, Wang T, Dong C, et al. Diagnostic evidence GAuge of single cells (DEGAS): A flexible deep-transfer learning framework for prioritizing cells in relation to disease. bioRxiv. 2021.
116.
Wu SC, Zhang Y. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability. J Biol Chem. 2011;286(32):28511–9.PubMedPubMedCentralCrossRef
117.
Wei Y, Chen YH, Li LY, Lang J, Yeh SP, Shi B, et al. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol. 2011;13(1):87–94.PubMedCrossRef
118.
Li Y, Gong J, Zhang L. PHD finger protein 19 expression in multiple myeloma: association with clinical features, induction therapy outcome, disease progression, and survival. J Clin Lab Anal. 2021;35(9):e23910.PubMedPubMedCentralCrossRef
119.
Holmes AB, Corinaldesi C, Shen Q, Kumar R, Compagno N, Wang Z, et al. Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome. J Exp Med. 2020;217(10).
120.
King HW, Orban N, Riches JC, Clear AJ, Warnes G, Teichmann SA, et al. Single-cell analysis of human B cell maturation predicts how antibody class switching shapes selection dynamics. Sci Immunol. 2021;6(56).
121.
Metadata
Title
Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer
Authors
Hussein Ghamlouch
Eileen M. Boyle
Patrick Blaney
Yubao Wang
Jinyoung Choi
Louis Williams
Michael Bauer
Daniel Auclair
Benedetto Bruno
Brian A. Walker
Faith E. Davies
Gareth J. Morgan
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-02185-1

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