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  • Review Article
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Targeting MYC in multiple myeloma

Abstract

Multiple myeloma (MM) is a plasma cell tumor marked by clonal evolution and preceded by a premalignant stage, which progresses via molecular pathway deregulation, including MYC activation. This activation relates to translocation or gain of the MYC locus and deregulation of upstream pathways such as IRF4, DIS3/LIN28B/let-7, or MAPK. Precision medicine is an approach to predict more accurately which treatment strategies for a particular disease will work in which groups of patients, in contrast to a “one-size-fits-all” approach. The knowledge of mechanisms responsible for MYC deregulation in MM enables identification of vulnerabilities and therapeutic targets in MYC-driven tumors. MYC can be targeted directly or indirectly, by interacting with several of its functions in cancer. Several such therapeutic strategies are evaluated in clinical trials in MM. In this review, we describe the mechanism of MYC activation in MM, the role of MYC in cancer progression, and the therapeutic options to targeting MYC.

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References

  1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046–60.

    Article  PubMed  CAS  Google Scholar 

  2. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA. SEER cancer statistics review, 1975-2013, National Cancer Institute Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016.

  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;113:5412–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood. 2009;113:5418–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Kuehl WM, Bergsagel PL. MYC addiction: a potential therapeutic target in MM. Blood. 2012;120:2351–2.

    Article  PubMed  CAS  Google Scholar 

  6. Vennstrom B, Sheiness D, Zabielski J, Bishop JM. Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29. J Virol. 1982;42:773–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  7. Sheiness D, Bishop JM. DNA and RNA from uninfected vertebrate cells contain nucleotide sequences related to the putative transforming gene of avian myelocytomatosis virus. J Virol. 1979;31:514–21.

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA. 1982;79:7824–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, Gilbert F, et al. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature. 1983;305:245–8.

    Article  PubMed  CAS  Google Scholar 

  10. Nau MM, Brooks BJ, Battey J, Sausville E, Gazdar AF, Kirsch IR, et al. L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature. 1985;318:69–73.

    Article  PubMed  CAS  Google Scholar 

  11. Shen-Ong GL, Keath EJ, Piccoli SP, Cole MD. Novel myc oncogene RNA from abortive immunoglobulin-gene recombination in mouse plasmacytomas. Cell. 1982;31:443–52.

    Article  PubMed  CAS  Google Scholar 

  12. Koh CM, Sabo A, Guccione E. Targeting MYC in cancer therapy: RNA processing offers new opportunities. Bioessays. 2016;38:266–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Atchley WR, Fitch WM. A natural classification of the basic helix-loop-helix class of transcription factors. Proc Natl Acad Sci USA. 1997;94:5172–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Lebofsky R, Walter JC. New Myc-anisms for DNA replication and tumorigenesis? Cancer Cell. 2007;12:102–3.

    Article  PubMed  CAS  Google Scholar 

  15. Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, et al. Non-transcriptional control of DNA replication by c-Myc. Nature. 2007;448:445–51.

    Article  PubMed  CAS  Google Scholar 

  16. Sabo A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, et al. Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature. 2014;511:488–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E, et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature. 2008;456:971–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wiegering A, Uthe FW, Jamieson T, Ruoss Y, Huttenrauch M, Kuspert M, et al. Targeting translation initiation bypasses signaling crosstalk mechanisms that maintain high MYC levels in colorectal cancer. Cancer Discov. 2015;5:768–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov. 2015;5:1024–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. McMahon SB. MYC and the control of apoptosis. Cold Spring Harb Perspect Med. 2014;4:a014407.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular dynamics. Immunity. 2007;27:190–202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429–57.

    Article  PubMed  CAS  Google Scholar 

  23. Victora GD, Dominguez-Sola D, Holmes AB, Deroubaix S, Dalla-Favera R, Nussenzweig MC. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood. 2012;120:2240–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M, Dustin ML, et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell. 2010;143:592–605.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Smith KG, Hewitson TD, Nossal GJ, Tarlinton DM. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur J Immunol. 1996;26:444–8.

    Article  PubMed  CAS  Google Scholar 

  26. Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity. 1998;8:363–72.

    Article  PubMed  CAS  Google Scholar 

  27. Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, et al. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med. 2004;200:967–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Lin Y, Wong K, Calame K. Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science. 1997;276:596–9.

    Article  PubMed  CAS  Google Scholar 

  29. Dominguez-Sola D, Victora GD, Ying CY, Phan RT, Saito M, Nussenzweig MC, et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat Immunol. 2012;13:1083–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Calado DP, Sasaki Y, Godinho SA, Pellerin A, Kochert K, Sleckman BP, et al. The cell cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol. 2012;13:1092–1100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Ott G, Rosenwald A, Campo E. Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification. Blood. 2013;122:3884–91.

    Article  PubMed  CAS  Google Scholar 

  32. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564–9.

    Article  PubMed  Google Scholar 

  33. Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann R, et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell. 2008 Feb;13:167–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Chng WJ, Huang GF, Chung TH, Ng SB, Gonzalez-Paz N, Troska-Price T, et al. Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia. 2011;25:1026–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 2014;28:1725–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997.

    Article  PubMed  CAS  Google Scholar 

  37. Avet-Loiseau H, Gerson F, Magrangeas F, Minvielle S, Harousseau JL, Bataille R, et al. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood. 2001;98:3082–6.

    Article  PubMed  CAS  Google Scholar 

  38. Shou Y, Martelli ML, Gabrea A, Qi Y, Brents LA, Roschke A, et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci USA. 2000;97:228–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B, et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell. 2006;9:313–25.

    Article  PubMed  CAS  Google Scholar 

  40. Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL, et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol. 2009;27:4585–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Lopez-Corral L, Sarasquete ME, Bea S, Garcia-Sanz R, Mateos MV, Corchete LA, et al. SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia. 2012;26:2521–9.

    Article  PubMed  CAS  Google Scholar 

  42. Manier S, Salem KZ, Park J, Landau DA, Getz G, Ghobrial IM. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol. 2016;14:100–13.

    Article  PubMed  CAS  Google Scholar 

  43. Chng WJ, Gonzalez-Paz N, Price-Troska T, Jacobus S, Rajkumar SV, Oken MM, et al. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia. 2008;22:2280–4.

    Article  PubMed  CAS  Google Scholar 

  44. Sears R, Leone G, DeGregori J, Nevins JR. Ras enhances Myc protein stability. Mol Cell. 1999;3:169–79.

    Article  PubMed  CAS  Google Scholar 

  45. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 2000;14:2501–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009;41:843–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Manier S, Powers JT, Sacco A, Glavey SV, Huynh D, Reagan MR, et al. The LIN28B/let-7 axis is a novel therapeutic pathway in multiple myeloma. Leukemia. 2017;31:853–60.

    Article  PubMed  CAS  Google Scholar 

  48. Segalla S, Pivetti S, Todoerti K, Chudzik MA, Giuliani EC, Lazzaro F, et al. The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA. Nucleic Acids Res. 2015;43:5182–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25:91–101.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol. 2015;33:3911–20.

    Article  PubMed  CAS  Google Scholar 

  51. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Mittrucker HW, Matsuyama T, Grossman A, Kundig TM, Potter J, Shahinian A, et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science. 1997;275:540–3.

    Article  PubMed  CAS  Google Scholar 

  53. Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T, et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol. 2006;7:773–82.

    Article  PubMed  CAS  Google Scholar 

  54. Shaffer AL, Emre NC, Lamy L, Ngo VN, Wright G, Xiao W, et al. IRF4 addiction in multiple myeloma. Nature. 2008;454:226–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Felsher DW, Bishop JM. Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc Natl Acad Sci USA. 1999;96:3940–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Zeller KI, Zhao X, Lee CW, Chiu KP, Yao F, Yustein JT, et al. Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci USA. 2006;103:17834–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Kress TR, Sabo A, Amati B. MYC: connecting selective transcriptional control to global RNA production. Nat Rev Cancer. 2015;15:593–607.

    Article  PubMed  CAS  Google Scholar 

  58. 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;151:56–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012;151:68–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452:230–3.

    Article  PubMed  CAS  Google Scholar 

  61. David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463:364–8.

    Article  PubMed  CAS  Google Scholar 

  62. Koh CM, Bezzi M, Low DH, Ang WX, Teo SX, Gay FP, et al. MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature. 2015;523:96–100.

    Article  PubMed  CAS  Google Scholar 

  63. Arabi A, Wu S, Ridderstrale K, Bierhoff H, Shiue C, Fatyol K, et al. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nat Cell Biol. 2005;7:303–10.

    Article  PubMed  CAS  Google Scholar 

  64. Grandori C, Gomez-Roman N, Felton-Edkins ZA, Ngouenet C, Galloway DA, Eisenman RN, et al. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol. 2005;7:311–8.

    Article  PubMed  CAS  Google Scholar 

  65. Pourdehnad M, Truitt ML, Siddiqi IN, Ducker GS, Shokat KM, Ruggero D. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc Natl Acad Sci USA. 2013;110:11988–93.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev. 2001;15:2852–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. de Alboran IM, O’Hagan RC, Gartner F, Malynn B, Davidson L, Rickert R, et al. Analysis of C-MYC function in normal cells via conditional gene-targeted mutation. Immunity. 2001;14:45–55.

    Article  PubMed  Google Scholar 

  68. Prathapam T, Tegen S, Oskarsson T, Trumpp A, Martin GS. Activated Src abrogates the Myc requirement for the G0/G1 transition but not for the G1/S transition. Proc Natl Acad Sci USA. 2006;103:2695–2700.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Mateyak MK, Obaya AJ, Sedivy JM. c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol. 1999;19:4672–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Santoni-Rugiu E, Falck J, Mailand N, Bartek J, Lukas J. Involvement of Myc activity in a G(1)/S-promoting mechanism parallel to the pRb/E2F pathway. Mol Cell Biol. 2000;20:3497–509.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, et al. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol Cell. 2001;8:105–13.

    Article  PubMed  CAS  Google Scholar 

  72. Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B. Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. EMBO J. 1996;15:6595–604.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Martins CP, Berns A. Loss of p27(Kip1) but not p21(Cip1) decreases survival and synergizes with MYC in murine lymphomagenesis. EMBO J. 2002;21:3739–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999;1:193–9.

    Article  PubMed  CAS  Google Scholar 

  75. O’Hagan RC, Ohh M, David G, de Alboran IM, Alt FW, Kaelin WG Jr., et al. Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes Dev. 2000;14:2185–91.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008;105:18782–7.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature. 2004;432:307–15.

    Article  PubMed  CAS  Google Scholar 

  79. Martin-Subero JI, Odero MD, Hernandez R, Cigudosa JC, Agirre X, Saez B, et al. Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas. Genes Chromosomes Cancer. 2005;43:414–23.

    Article  PubMed  CAS  Google Scholar 

  80. Knezevich S, Ludkovski O, Salski C, Lestou V, Chhanabhai M, Lam W, et al. Concurrent translocation of BCL2 and MYC with a single immunoglobulin locus in high-grade B-cell lymphomas. Leukemia. 2005;19:659–63.

    Article  PubMed  CAS  Google Scholar 

  81. Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985;318:533–8.

    Article  PubMed  CAS  Google Scholar 

  82. Strasser A, Harris AW, Bath ML, Cory S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature. 1990;348:331–3.

    Article  PubMed  CAS  Google Scholar 

  83. Letai A, Sorcinelli MD, Beard C, Korsmeyer SJ. Antiapoptotic BCL-2 is required for maintenance of a model leukemia. Cancer Cell. 2004;6:241–9.

    Article  PubMed  CAS  Google Scholar 

  84. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016;352:227–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Snead NM, Wu X, Li A, Cui Q, Sakurai K, Burnett JC, et al. Molecular basis for improved gene silencing by Dicer substrate interfering RNA compared with other siRNA variants. Nucleic Acids Res. 2013;41:6209–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Holien T, Vatsveen TK, Hella H, Waage A, Sundan A. Addiction to c-MYC in multiple myeloma. Blood. 2012;120:2450–3.

    Article  PubMed  CAS  Google Scholar 

  87. Wang H, Teriete P, Hu A, Raveendra-Panickar D, Pendelton K, Lazo JS, et al. Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids. Oncotarget. 2015;6:32380–95.

    PubMed  PubMed Central  Google Scholar 

  88. Hart JR, Roberts TC, Weinberg MS, Morris KV, Vogt PK. MYC regulates the non-coding transcriptome. Oncotarget. 2014;5:12543–54.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Stellas D, Szabolcs M, Koul S, Li Z, Polyzos A, Anagnostopoulos C, et al. Therapeutic effects of an anti-Myc drug on mouse pancreatic cancer. J Natl Cancer Inst. 2014;106:12.

    Article  CAS  Google Scholar 

  90. Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, et al. c-Myc regulates transcriptional pause release. Cell. 2010;141:432–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. 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;153:320–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Amorim S, Stathis A, Gleeson M, Iyengar S, Magarotto V, Leleu X, et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016;3:e196–204.

    Article  PubMed  Google Scholar 

  95. Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Cote A, Leblanc Y, et al. Identification of a benzoisoxazoloazepine inhibitor (CPI-0610) of the bromodomain and extra-terminal (BET) family as a candidate for human clinical trials. J Med Chem. 2016;59:1330–9.

    Article  PubMed  CAS  Google Scholar 

  96. Siu KT, Ramachandran J, Yee AJ, Eda H, Santo L, Panaroni C, 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;31:1760–9.

    Article  PubMed  CAS  Google Scholar 

  97. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759–69.

    Article  PubMed  CAS  Google Scholar 

  99. Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–5.

    Article  PubMed  CAS  Google Scholar 

  100. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343:305–9.

    Article  PubMed  CAS  Google Scholar 

  101. Hsu TY, Simon LM, Neill NJ, Marcotte R, Sayad A, Bland CS, et al. The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature. 2015;525:384–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature. 2014;513:65–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Thumma SC, Jacobson BA, Patel MR, Konicek BW, Franklin MJ, Jay-Dixon J, et al. Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells. Cancer Gene Ther. 2015;22:396–401.

    Article  PubMed  CAS  Google Scholar 

  104. Haghighat A, Mader S, Pause A, Sonenberg N. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J. 1995;14:5701–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 1999;13:1422–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Jones RM, Branda J, Johnston KA, Polymenis M, Gadd M, Rustgi A, et al. An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc. Mol Cell Biol. 1996;16:4754–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Rosenwald IB, Rhoads DB, Callanan LD, Isselbacher KJ, Schmidt EV. Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc. Proc Natl Acad Sci USA. 1993;90:6175–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Deng C, Lipstein MR, Scotto L, Jirau Serrano XO, Mangone MA, Li S, et al. Silencing c-Myc translation as a therapeutic strategy through targeting PI3K delta and CK1 epsilon in hematological malignancies. Blood 2016;129:88–99.

  109. Rodrigo CM, Cencic R, Roche SP, Pelletier J, Porco JA. Synthesis of rocaglamide hydroxamates and related compounds as eukaryotic translation inhibitors: synthetic and biological studies. J Med Chem. 2012;55:558–62.

    Article  PubMed  CAS  Google Scholar 

  110. Bordeleau ME, Robert F, Gerard B, Lindqvist L, Chen SM, Wendel HG, et al. Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008;118:2651–60.

    PubMed  PubMed Central  CAS  Google Scholar 

  111. Manier S, Huynh D, Shen Y, Salem K, Ebright R, Park J, et al. Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma. Sci Transl Med. 2017;9:pii: eaal2668.

    Article  Google Scholar 

  112. Ruggero D. Translational control in cancer etiology. Cold Spring Harb Perspect Biol. 2013;5:a012336.

  113. Drygin D, Lin A, Bliesath J, Ho CB, O’Brien SE, Proffitt C, et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 2011;71:1418–30.

    Article  PubMed  CAS  Google Scholar 

  114. Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell. 2012;22:51–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Lee HC, Wang H, Baladandayuthapani V, Lin H, He J, Jones RJ, et al. RNA polymerase I inhibition with CX-5461 as a novel therapeutic strategy to target MYC in multiple myeloma. Br J Haematol. 2017;177:80–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515:563–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3:1052–62.

    Article  PubMed  CAS  Google Scholar 

  118. Fu LL, Tian M, Li X, Li JJ, Huang J, Ouyang L, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6:5501–16.

    PubMed  PubMed Central  Google Scholar 

  119. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906–17.

    Article  PubMed  CAS  Google Scholar 

  120. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311–20.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Jovanović, K.K., Roche-Lestienne, C., Ghobrial, I.M. et al. Targeting MYC in multiple myeloma. Leukemia 32, 1295–1306 (2018). https://doi.org/10.1038/s41375-018-0036-x

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