Advertisement

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

  • B. Zhai
  • C. Hou
  • R. Xu
  • Y. Fang
  • N. Ma
  • C. Xing
  • X. Wang
  • H. Xiao
  • G. Chen
  • G. HanEmail author
  • R. WangEmail author
Research Article

Abstract

Purpose

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.

Methods/patients

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.

Results

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.

Conclusions

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.

Keywords

Gm6377 Myc B Cells Plasma cells Multiple myeloma 

Notes

Funding

This work was supported by the  National Nature and Science Funds under Grant numbers 31770956 and 81471529 and Beijing Natural Science Foundation under Grant number 7182121.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interest.

Research involving human participants and animals

All procedures performed in studies involving human participants and animals were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12094_2019_2280_MOESM1_ESM.pdf (187 kb)
Supplementary file1 (PDF 186 kb)

References

  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  3. 3.
    Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015;15:160–71.CrossRefGoogle Scholar
  4. 4.
    Recaldin T, Fear DJ. Transcription factors regulating B cell fate in the germinal centre. Clin Exp Immunol. 2015;183:65–75.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  10. 10.
    Mackay F, Schneider P. Cracking the BAFF code. Nat Rev Immunol. 2009;9:491–502.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  13. 13.
    Chesi M, Bergsagel PL. Molecular pathogenesis of multiple myeloma: basic and clinical updates. Int J Hematol. 2013;97:313–23.CrossRefGoogle Scholar
  14. 14.
    Bianchi G, Richardson PG, Anderson KC. Promising therapies in multiple myeloma. Blood. 2015;126:300–10.CrossRefGoogle Scholar
  15. 15.
    Avigan D, Rosenblatt J. Current treatment for multiple myeloma. N Engl J Med. 2014;371:961–2.CrossRefGoogle Scholar
  16. 16.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.CrossRefGoogle Scholar
  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.Google Scholar
  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.PubMedPubMedCentralGoogle Scholar
  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.  https://doi.org/10.1038/leu.2012.269.CrossRefPubMedPubMedCentralGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.  https://doi.org/10.1080/10428194.2019.1590572.CrossRefPubMedGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  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.CrossRefGoogle Scholar
  33. 33.
    Schebesta M, Heavey B, Busslinger M. Transcriptional control of B-cell development. Curr Opin Immunol. 2002;14:216–23.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2020

Authors and Affiliations

  1. 1.Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain DisordersBeijing Institute of Brain Disorders, Capital Medical UniversityBeijingChina
  2. 2.Department of Geriatric Hematology, Nanlou DivisionChinese PLA General Hospital, National Clinical Research Center for Geriatric DiseasesBeijingChina
  3. 3.Institute of Military Cognition and Brain SciencesBeijingChina
  4. 4.Department of RheumatologyFirst Hospital of Jilin UniversityChangchunChina
  5. 5.Staidson (Beijing) Biopharmaceuticals Co., Ltd BeijingChina
  6. 6.State Key Laboratory of Toxicology and Medical CountermeasuresInstitute of Pharmacology and ToxicologyBeijingChina

Personalised recommendations