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Review

Targeting transcription factors in multiple myeloma: evolving therapeutic strategies

, , , , ORCID Icon &
Pages 445-462 | Received 10 Feb 2019, Accepted 05 Apr 2019, Published online: 16 Apr 2019

References

  • Darnell JE. Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002;2:740–749.
  • Stower H. Gene regulation: from genetic variation to phenotype via chromatin. Nat Rev Genet. 2013;14:824.
  • Kumar SK, Callander NS, Alsina M, et al. NCCN guidelines insights: multiple myeloma, version 3.2018. J Natl Compr Canc Netw. 2018;16:11–20.
  • Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012;12:335–348.
  • Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969;208:1680–1685.
  • Hagenbuchner J, Ausserlechner MJ. Targeting transcription factors by small compounds—current strategies and future implications. Biochem Pharmacol. 2016;107:1–13.
  • Waddington CH. Towards a theoretical biology. Nature. 1968;218:525–527.
  • Feinberg AP, Koldobskiy MA, Göndör A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016;17:284–299.
  • Fujisawa T, Filippakopoulos P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Biol. 2017;18:246–262.
  • Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230–242.
  • Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer. Cell. 2017;168:629–643.
  • O’Brien P, Morin P, Ouellette RJ, et al. The Pax-5 gene: A pluripotent regulator of B-cell differentiation and cancer disease. Cancer Res. 2011;71:7345–7350.
  • Paiva B, Puig N, Cedena MT, et al. Differentiation stage of myeloma plasma cells: biological and clinical significance. Leukemia. 2017;31:382–392.
  • Proulx M, Cayer M-P, Drouin M, et al. Overexpression of PAX5 induces apoptosis in multiple myeloma cells. Int J Hematol. 2010;92:451–462.
  • Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol. 2010;11:114–120.
  • Hideshima T, Mitsiades C, Ikeda H, et al. A proto-oncogene BCL6 is up-regulated in the bone marrow microenvironment in multiple myeloma cells. Blood. 2010;115:3772–3775.
  • McCoull W, Abrams RD, Anderson E, et al. Discovery of pyrazolo[1,5- a]pyrimidine B-cell lymphoma 6 (BCL6) binders and optimization to high affinity macrocyclic inhibitors. J Med Chem. 2017;60:4386–4402.
  • Kometani K, Nakagawa R, Shinnakasu R, et al. Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation. Immunity. 2013;39:136–147.
  • Hung K-H, Su S-T, Chen C-Y, et al. Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells. Cell Death Differ. 2016;23:1175–1184.
  • Iwakoshi NN, Lee A-H, Glimcher LH. The X-box binding protein-1 transcription factor is required for plasma cell differentiation and the unfolded protein response. Immunol Rev. 2003;194:29–38.
  • Bagratuni T, Wu P, Castro D GD, et al. XBP1s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments. Blood. 2010;116:250–253.
  • Carrasco DEER, Sukhdeo K, Protopopova M, et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell. 2007;11:349–360.
  • Leung-Hagesteijn C, Erdmann N, Cheung G, et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell. 2013;24:289–304.
  • Xu G, Liu K, Anderson J, et al. Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation. Blood. 2012;119:4205–4214.
  • Bae J, Hideshima T, Zhang GL, et al. Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma. Leukemia. 2018;32:752–764.
  • Nooka AK, Wang ML, Yee AJ, et al. Assessment of Safety and Immunogenicity of PVX-410 vaccine with or without lenalidomide in patients with smoldering multiple myeloma: a nonrandomized clinical trial. JAMA Oncol. 2018;4:e183267.
  • Mimura N, Fulciniti M, Gorgun G, et al. Blockade of XBP1 splicing by inhibition of IRE1 is a promising therapeutic option in multiple myeloma. Blood. 2012;119:5772–5781.
  • Mittrücker HW, Matsuyama T, Grossman A, et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science. 1997;275:540–543.
  • Iida S, Rao PH, Butler M, et al. Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nat Genet. 1997;17:226–230.
  • Shaffer AL, Emre NCT, Lamy L, et al. IRF4 addiction in multiple myeloma. Nature. 2008;454:226–231.
  • Heintel D, Zojer N, Schreder M, et al. Expression of MUM1/IRF4 mRNA as a prognostic marker in patients with multiple myeloma. Leukemia. 2008;22:441–445.
  • Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343:305–309.
  • Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–305.
  • Fedele PL, Willis SN, Liao Y, et al. IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos. Blood. 2018;132:2166–2178.
  • Zhu YX, Braggio E, Shi C-X, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood. 2014;124:536–545.
  • Li S, Fu J, Wang H, et al. IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation. Blood Adv. 2018;2:492–504.
  • Liu A, Li S, Donnenberg V, et al. Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation. Haematologica. 2018;103:1688–1697.
  • Zhang X, Lee HC, Shirazi F, et al. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia. 2018;32:2224–2239.
  • Morelli E, Leone E, Cantafio MEG, et al. Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo. Leukemia. 2015;29:2173–2183.
  • Conery AR, Centore RC, Neiss A, et al. Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma. Elife. 2016;5.e10483
  • Lasko LM, Jakob CG, Edalji RP, et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature. 2017;550:128–132.
  • Ishiguro K, Kitajima H, Niinuma T, et al. DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling. Haematologica. 2019;104:155–165.
  • Calado DP, Sasaki Y, Godinho SA, et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol. 2012;13:1092–1100.
  • Affer M, Chesi M, Chen W-DG, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 2014;28:1725–1735.
  • Walker BA, Wardell CP, Murison A, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997.
  • Avet-Loiseau H, Gerson F, Magrangeas F, et al. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood. 2001;98:3082–3086.
  • López-Corral L, Sarasquete ME, Beà S, et al. SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia. 2012;26:2521–2529.
  • Chng W-J, Huang GF, Chung TH, et al. Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia. 2011;25:1026–1035.
  • Chng WJ, Gonzalez-Paz N, Price-Troska T, et al. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia. 2008;22:2280–2284.
  • Chesi M, Bergsagel PL. Advances in the pathogenesis and diagnosis of multiple myeloma. Int J Lab Hematol. 2015;37(Suppl 1):108–114.
  • Jovanović KK, Roche-Lestienne C, Ghobrial IM, et al. Targeting MYC in multiple myeloma. Leukemia. 2018;32:1295–1306.
  • Holien T, Vatsveen TK, Hella H, et al. Addiction to c-MYC in multiple myeloma. Blood. 2012;120:2450–2453.
  • Wang H, Teriete P, Hu A, et al. Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids. Oncotarget. 2015;6:32380–32395.
  • Hart JR, Roberts TC, Weinberg MS, et al. MYC regulates the non-coding transcriptome. Oncotarget. 2014;5:12543–12554.
  • Tolcher AW, Papadopoulos KP, Patnaik A, et al. Safety and activity of DCR-MYC, a first-in-class Dicer-substrate small interfering RNA (DsiRNA) targeting MYC, in a phase I study in patients with advanced solid tumors. J Clin Oncol. 2015;33:11006.
  • Delmore JEE, Issa GCC, Lemieux MEE, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–917.
  • Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108:16669–16674.
  • Chaidos A, Caputo V, Gouvedenou K, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014;123:697–705.
  • Siegel MB, Liu SQ, Davare MA, et al. Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma. Oncotarget. 2015;6:18921–18932.
  • Siu KT, Ramachandran J, Yee AJ, et al. Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma. Leukemia. 2017;31:1760–1769.
  • Xiao G, Fu J. NF-κB and cancer: a paradigm of Yin-Yang. Am J Cancer Res. 2011;1:192–221.
  • Roy P, Sarkar U, Basak S. The NF-κB activating pathways in multiple myeloma. Biomedicines. 2018;6:59.
  • Hu J, Hu W-X. Targeting signaling pathways in multiple myeloma: pathogenesis and implication for treatments. Cancer Lett. 2018;414:214–221.
  • Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018;19:370–381.
  • Murray MY, Zaitseva L, Auger MJ, et al. Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma. Cell Cycle. 2015;14.
  • Richardson PG, Bensinger WI, Huff CA, et al. Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results. Br J Haematol. 2018;180:821–830.
  • Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9:798–809.
  • Le Gouill S, Pellat-Deceunynck C, Harousseau J-L, et al. Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells. Leukemia. 2002;16:1664–1667.
  • Nelson EA, Walker SR, Kepich A, et al. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood. 2008;112:5095–5102.
  • Ko J-H, Ho Baek S, Nam D, et al. 3-formylchromone inhibits proliferation and induces apoptosis of multiple myeloma cells by abrogating STAT3 signaling through the induction of PIAS3. Immunopharmacol Immunotoxicol. 2016;38:334–343.
  • Hayakawa F, Sugimoto K, Harada Y, et al. A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases. Blood Cancer J. 2013;3:e166–e166.
  • Scuto A, Krejci P, Popplewell L, et al. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia. 2011;25:538–550.
  • Honda A, Kuramoto K, Niwa T, et al. NS-018 reduces myeloma cell proliferation and suppresses osteolysis through inhibition of the JAK2 and Src signaling pathways. Blood Cancer J. 2018;8:62.
  • Amodio N, Bellizzi D, Leotta M, et al. miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells. Cell Cycle. 2013;12:3650–3662.
  • Eferl R, Wagner EF. AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer. 2003;3:859–868.
  • Grötsch B, Brachs S, Lang C, et al. The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells. J Exp Med. 2014;211:2199–2212.
  • Ubieta K, Garcia M, Grötsch B, et al. Fra-2 regulates B cell development by enhancing IRF4 and foxo1 transcription. J Exp Med. 2017;214:2059–2071.
  • Wagner EF. Bone development and inflammatory disease is regulated by AP-1 (Fos/Jun). Ann Rheum Dis. 2010;69:i86–i88.
  • Hurt EM, Wiestner A, Rosenwald A, et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell. 2004;5:191–199.
  • Annunziata CM, Hernandez L, Davis RE, et al. A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression. Blood. 2011;117:2396–2404.
  • Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137:873–886.
  • Qiang Y-W, Ye S, Chen Y, et al. MAF protein mediates innate resistance to proteasome inhibition therapy in multiple myeloma. Blood. 2016;128:2919–2930.
  • Robbiani DF, Colon K, Ely SS, et al. Osteopontin dysregulation and lytic bone lesions in multiple myeloma. Hematol Oncol. 2007;25:16–20.
  • Herath NI, Rocques N, Garancher A, et al. GSK3-mediated MAF phosphorylation in multiple myeloma as a potential therapeutic target. Blood Cancer J. 2014;4:e175.
  • Podar K, Raab MS, Tonon G, et al. Up-regulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma. Cancer Res. 2007;67:1680–1688.
  • Miannay B, Minvielle S, Roux O, et al. Logic programming reveals alteration of key transcription factors in multiple myeloma. Sci Rep. 2017;7:9257.
  • Fan F, Bashari MHH, Morelli E, et al. The AP-1 transcription factor JunB is essential for multiple myeloma cell proliferation and drug resistance in the bone marrow microenvironment. Leukemia. 2017;31:1570–1581.
  • Bykov VJN, Eriksson SE, Bianchi J, et al. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer. 2018;18:89–102.
  • Chng WJ, Price-Troska T, Gonzalez-Paz N, et al. Clinical significance of TP53 mutation in myeloma. Leukemia. 2007;21:582–584.
  • Drach J, Ackermann J, Fritz E, et al. Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood. 1998;92:802–809.
  • Chang H, Qi C, Yi Q-L, et al. p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood. 2005;105:358–360.
  • Chang H, Sloan S, Li D, et al. Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions. Br J Haematol. 2004;127:280–284.
  • Billecke L, Penas EMM, May AM, et al. Similar incidences of TP53 deletions in extramedullary organ infiltrations, soft tissue and osteolyses of patients with multiple myeloma. Anticancer Res. 2012;32:2031–2034.
  • Teoh G, Urashima M, Ogata A, et al. MDM2 protein overexpression promotes proliferation and survival of multiple myeloma cells. Blood. 1997;90:1982–1992.
  • Stanganelli C, Arbelbide J, Fantl DB, et al. DNA methylation analysis of tumor suppressor genes in monoclonal gammopathy of undetermined significance. Ann Hematol. 2010;89:191–199.
  • Hodge DR, Peng B, Cherry JC, et al. Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res. 2005;65:4673–4682.
  • Jones RJ, Bjorklund CC, Baladandayuthapani V, et al. Drug resistance to inhibitors of the human double minute-2 E3 ligase is mediated by point mutations of p53, but can be overcome with the p53 targeting agent RITA. Mol Cancer Ther. 2012;11:2243–2253.
  • Lambert JMR, Gorzov P, Veprintsev DB, et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009;15:376–388.
  • Tessoulin B, Descamps G, Moreau P, et al. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood. 2014;124:1626–1636.
  • Saha MN, Qiu L, Chang H. Targeting p53 by small molecules in hematological malignancies. J Hematol Oncol. 2013;6:23.
  • Tan NY, Khachigian LM. Sp1 phosphorylation and its regulation of gene transcription. Mol Cell Biol. 2009;29:2483–2488.
  • Fulciniti M, Amin S, Nanjappa P, et al. Significant biological role of sp1 transactivation in multiple myeloma. Clin Cancer Res. 2011;17:6500–6509.
  • Otjacques E, Binsfeld M, Rocks N, et al. Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors. de Carvalho DP, editor. PLoS One. 2013. 8, e62818.
  • Karki K, Harishchandra S, Safe S. Bortezomib targets sp transcription factors in cancer cells. Mol Pharmacol. 2018;94:1187–1196.
  • D’Souza S, Del Prete D, Jin S, et al. Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease. Blood. Internet]. 2011 [cited 2019 Jan 20];118:6871–6880. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22042697
  • Petrusca DN, Toscani D, Wang F-M, et al. Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis. J Hematol Oncol. 2018;11:123.
  • Ramji DP, Foka P. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J. 2002;365:561–575.
  • Pal R, Janz M, Galson DL, et al. C/EBPbeta regulates transcription factors critical for proliferation and survival of multiple myeloma cells. Blood. 2009;114:3890–3898.
  • Zhu YX, Shi C-X, Bruins LA, et al. Loss of FAM46C promotes cell survival in myeloma. Cancer Res. 2017;77:4317–4327.
  • Li S, Pal R, Monaghan SA, et al. IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM. Blood. 2011;117:5157–5165.
  • Wang LH, Yang XY, Zhang X, et al. Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARgamma cross talk with NF-kappaB and C/EBP. Blood. 2007;110:4373–4384.
  • Fulciniti M, Lin CY, Samur MK, et al. Non-overlapping control of transcriptome by promoter- and super-enhancer-associated dependencies in multiple myeloma. Cell Rep. 2018;25:3693–3705.e6.
  • Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–732.
  • Zhang J, Sattler M, Tonon G, et al. Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma. Cancer Res. 2009;69:5082–5090.
  • Colla S, Tagliaferri S, Morandi F, et al. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 alpha (HIF-1alpha) activity: involvement in myeloma-induced angiogenesi. Blood. 2007;110:4464–4475.
  • Storti P, Bolzoni M, Donofrio G, et al. Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction. Leukemia. 2013;27:1697–1706.
  • Maiso P, Huynh D, Moschetta M, et al. Metabolic signature identifies novel targets for drug resistance in multiple myeloma. Cancer Res. 2015;75:2071–2082.
  • Borsi E, Perrone G, Terragna C, et al. Hypoxia inducible factor-1 alpha as a therapeutic target in multiple myeloma. Oncotarget. 2014;5:1779–1792.
  • Imperato MR, Cauchy P, Obier N, et al. The RUNX1–PU.1 axis in the control of hematopoiesis. Int J Hematol. 2015;101:319–329.
  • Tatetsu H, Ueno S, Hata H, et al. Down-regulation of PU.1 by methylation of distal regulatory elements and the promoter Is required for myeloma cell growth. Cancer Res. 2007;67: 5328–5336.
  • Ueno N, Nishimura N, Ueno S, et al. PU.1 acts as tumor suppressor for myeloma cells through direct transcriptional repression of IRF4. Oncogene. 2017;36:4481–4497.
  • Endo S, Amano M, Nishimura N, et al. Immunomodulatory drugs act as inhibitors of DNA methyltransferases and induce PU.1 up-regulation in myeloma cells. Biochem Biophys Res Commun. 2016;469:236–242.
  • Anderson G, Gries M, Kurihara N, et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of. PU1 Blood. 2006;107:3098–3105.
  • Pal R, Monaghan SA, Hassett AC, et al. Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia. Blood.. 2010;115:605–614.
  • Pawlyn C, Kaiser MF, Heuck C, et al. The spectrum and clinical impact of epigenetic modifier mutations in myeloma. Clin Cancer Res. 2016;22:5783–5794.
  • Ohguchi H, Hideshima T, Anderson KC. The biological significance of histone modifiers in multiple myeloma: clinical applications. Blood Cancer J. 2018;8:83.
  • Heuck CJ, Mehta J, Bhagat T, et al. Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis. J Immunol. 2013;190:2966–2975.
  • Kaiser MF, Johnson DC, Wu P, et al. Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma. Blood. 2013;122:219–226.
  • Ohguchi H, Hideshima T, Bhasin MK, et al. The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival. Nat Commun. 2016;7:10258.
  • Ohguchi H, Harada T, Sagawa M, et al. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia. 2017;31:2661–2669.
  • Zeng D, Liu M, Pan J. Blocking EZH2 methylation transferase activity by GSK126 decreases stem cell-like myeloma cells. Oncotarget. 2017;8:3396–3411.
  • Adamik J, Jin S, Sun Q, et al. EZH2 or HDAC1 inhibition reverses multiple myeloma-induced epigenetic suppression of osteoblast differentiation. Mol Cancer Res. 2017;15:405–417.
  • Gullà A, Hideshima T, Bianchi G, et al. Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia. 2018;32:996–1002.
  • Harada T, Hideshima T, Anderson KC. Histone deacetylase inhibitors in multiple myeloma: from bench to bedside. Int J Hematol. 2016;104:300–309.
  • Minami J, Suzuki R, Mazitschek R, et al. Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia. 2014;28:680–689.
  • Vallabhapurapu SD, Noothi SK, Pullum DA, et al. Transcriptional repression by the HDAC4–relB–p52 complex regulates multiple myeloma survival and growth. Nat Commun. 2015;6:8428.
  • Kikuchi S, Suzuki R, Ohguchi H, et al. Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma. Leukemia. 2015;29:1918–1927.
  • Amodio N, Stamato MA, Gullà AM, et al. Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma. Mol Cancer Ther. 2016;15:1364–1375.
  • Kawaguchi Y, Kovacs JJ, McLaurin A, et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 2003;115:727–738.
  • Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A. 2005;102:8567–8572.
  • Santo L, Hideshima T, Kung AL, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012;119:2579–2589.
  • Mishima Y, Santo L, Eda H, et al. Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br J Haematol. 2015;169:423–434.
  • Cea M, Cagnetta A, Adamia S, et al. Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells. Blood. 2016;127:1138–1150.
  • Vaquerizas JM, Kummerfeld SK, Teichmann SA, et al. A census of human transcription factors: function, expression and evolution. Nat Rev Genet. 2009;10:252–263.
  • San-Miguel JF, Richardson PG, Günther A, et al. Phase ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol. 2013;31:3696–3703.

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