Gm6377 suppressed SP 2/0 xenograft tumor by down-regulating Myc transcription



Disturbed process of B-cell differentiation into plasmablasts (PBs)/plasma cells (PCs) is involved in multiple myeloma (MM). New strategies will be required to eliminate the MM cell clone for a long-term disease control. Because of its PB-like characteristics, the mus musculus myeloma SP 2/0 cell line was used in this study to search novel targets for PBs/PCs.


Affymetrix microarrays and RNA-sequencing assays were used to search a novel different molecule (Gm6377) between PBs/PCs and mature B cells. Cell counting kit-8 (CCK8), flow cytometry (FACS), xenograft mouse model, and the luciferase reporter system were used to assess the effect of Gm6377 on SP 2/0 cell proliferation, cell cycle, tumor growth, and Myc promoter activation, respectively.


We found that B cells expressed a high level of Gm6377 mRNA, whereas Gm6377 mRNA was decreased in PCs. In addition, SP 2/0 cells also expressed low levels of Gm6377 mRNA. Critically, Gm6377 overexpression suppressed SP 2/0 cell proliferation but not cell cycle. Furthermore, Gm6377 overexpression suppressed tumor progression in the SP 2/0 xenograft mouse model. Finally, we found that Gm6377 suppressed SP 2/0 cell proliferation by reducing the activation of the Myc promoter.


These results suggest that Gm6377 suppresses myeloma SP 2/0 cell growth by suppressing Myc. Thus, modulation of Gm6377 may be a potential therapeutic way to treat MM.

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Data availability

The datasets generated and/or analyzed during the current study are available in the ArrayExpress repository, - 7106, 7109, 7110, 7112, and 7139.


  1. 1.

    Horcher M, Souabni A, Busslinger M. Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis. Immunity. 2001;14:779–90.

  2. 2.

    Kitano M, Moriyama S, Ando Y, AHikida M, Mori Y, Kurosaki T, et al. Bc protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 2011;34:961–72.

  3. 3.

    Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015;15:160–71.

  4. 4.

    Recaldin T, Fear DJ. Transcription factors regulating B cell fate in the germinal centre. Clin Exp Immunol. 2015;183:65–75.

  5. 5.

    Taubenheim N, Tarlinton DM, Crawford S, Corcoran LM, Hodgkin PD, Nutt SL. High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency. J Immunol. 2012;189:3328–38.

  6. 6.

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

  7. 7.

    Lin KI, Lin Y, Calame K. Repression of c-myc Is Necessary but Not Sufficient for Terminal Differentiation of B Lymphocytes In Vitro. Mol Cell Biol. 2000;20:8684–95.

  8. 8.

    Klein U, Tu Y, Stolovitzky GA, Keller JL, Haddad J, Miljkovic V, et al. Transcriptional analysis of the B cell germinal center reaction. Proc Natl Acad Sci USA. 2003;100:2639–44.

  9. 9.

    Ma N, Xing C, Xiao H, He Y, Han G, Chen G, et al. BAFF Suppresses IL-15 Expression in B Cells. J Immunol. 2014;192:4192–201.

  10. 10.

    Mackay F, Schneider P. Cracking the BAFF code. Nat Rev Immunol. 2009;9:491–502.

  11. 11.

    Cancro MP, D'Cruz DP, Khamashta MA. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest. 2009;119:1066–73.

  12. 12.

    Carbonatto M, Yu P, Bertolinom M, Vigna E, Steidler S, Fava L, et al. Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept. Toxicol Sci. 2008;105:200–10.

  13. 13.

    Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol. 2013;97:313–23.

  14. 14.

    Bianchi G, Richardson PG, Anderson KC. Promising therapies in multiple myeloma. Blood. 2015;126:300–10.

  15. 15.

    Avigan D, Rosenblatt J. Current treatment for multiple myeloma. N Engl J Med. 2014;371:961–2.

  16. 16.

    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

  17. 17.

    Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma a randomised, open-label, phase 3 trial. Lancet 2019;140–6736.

  18. 18.

    Gerecke C, Fuhrmann S, Strifler S, Schmidt-Hieber M, Einsele H, Knop S. The diagnosis and treatment of multiple myeloma. Dtsch Arztebl Int. 2016;113:470–6.

  19. 19.

    Min DJ, Ezponda T, Kim MK, Will CM, Martinez-Garcia E, Popovic R, et al. MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC. Leukemia. 2012.

  20. 20.

    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.

  21. 21.

    Liu X, Zhang Y, Wang Z, Wang X, Zhu G, Han G, et al. Metabotropic glutamate receptor 3 is involved in B-cell-related tumor apoptosis. Int J Oncol. 2016;49:1469–78.

  22. 22.

    Xu R, Fang Y, Hou C, Zhai B, Jiang Z, Ma N, et al. BC094916 suppressed SP 2/0 xenograft tumor by down-regulating Creb1 and Bcl2 transcription. Cancer Cell Int. 2018;18:138.

  23. 23.

    Wang X, Wei Y, Liu X, Xing C, Han G, Chen G, et al. IL-15-secreting gdT cells induce memory T cells in experimental allergic encephalomyelitis (EAE) mice. Mol Immunol. 2015;66:402–8.

  24. 24.

    Zhu G, Liu X, Fang Y, Zhai B, Xu R, Han G, et al. Increased mTOR cancels out the effect of reduced Xbp-1 on antibody secretion in IL-1a-deficient B cells. Cell Immunol. 2018;328:9–17.

  25. 25.

    Fang Y, Xu R, Zhai B, Hou C, Ma N, Wang L, et al. Gm40600 suppressed SP 2/0 isograft tumor by reducing Blimp1 and Xbp1 proteins. BMC Cancer. 2019;19:700.

  26. 26.

    Liu X, Zhang Y, Wei Y, Wang Z, Zhu G, Fang Y, et al. The E3 ubiquitin ligase Itch is required for B-cell differentiation. Sci Rep. 2019;9:421.

  27. 27.

    Zhai B, Hou C, Xu R, Fang Y, Xiao H, Chen G, et al. Loc108167440 suppressed myeloma cell growth by p53-mediated apoptosis. Leuk Lymphoma. 2019.

  28. 28.

    Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann T, 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;13:167–80.

  29. 29.

    Dorasamy MS, Choudhary B, Nellore K, Subramanya H, Wong PF. Dihydroorotate dehydrogenase inhibitors target c-Myc and arrest melanoma, myeloma and lymphoma cells at S-phase. J Cancer. 2017;8:3086–98.

  30. 30.

    Holien T, Misund K, Olsen OE, Baranowska KA, Buene G, Borset M, et al. MYC amplifications in myeloma cell lines: correlation with MYC-inhibitor efficacy. Oncotarget. 2015;6:22698–705.

  31. 31.

    Soodgupta D, Pan D, Cui G, Senpan A, Yang X, Lu L, et al. Small molecule Myc inhibitor conjugated to integrin-targeted nanoparticles extends survival in a mouse model of disseminated multiple myeloma. Mol Cancer Ther. 2015;14:1286–94.

  32. 32.

    Hartl M, Karagiannidis AI, Bister K. Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis. Oncogene. 2006;25:4043–55.

  33. 33.

    Schebesta M, Heavey B, Busslinger M. Transcriptional control of B-cell development. Curr Opin Immunol. 2002;14:216–23.

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Correspondence to G. Han or R. Wang.

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Zhai, B., Hou, C., Xu, R. et al. Gm6377 suppressed SP 2/0 xenograft tumor by down-regulating Myc transcription. Clin Transl Oncol (2020) doi:10.1007/s12094-019-02280-y

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  • Gm6377
  • Myc
  • B Cells
  • Plasma cells
  • Multiple myeloma