Role of MBD3-SOX2 axis in residual myeloma following pomalidomide

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Enhanced clonogenic potential and growth of pomalidomide-residual disease is SOX2 dependent.
Fig. 2: MBD3 mediated SOX2 enrichment of human MM cells in Pom exposed residual MM cells.


  1. 1.

    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.

    CAS  Article  Google Scholar 

  2. 2.

    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  Google Scholar 

  3. 3.

    Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164:811–21.

    CAS  Article  Google Scholar 

  4. 4.

    Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012;26:2326–35.

    CAS  Article  Google Scholar 

  5. 5.

    Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118:4771–9.

    CAS  Article  Google Scholar 

  6. 6.

    Xu Y, Li J, Ferguson GD, Mercurio F, Khambatta G, Morrison L, et al. Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases. Blood. 2009;114:338–45.

    CAS  Article  Google Scholar 

  7. 7.

    Yu H, Borsotti C, Schickel JN, Zhu S, Strowig T, Eynon EE, et al. A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production. Blood. 2017;129:959–69.

    CAS  Article  Google Scholar 

  8. 8.

    Das R, Strowig T, Verma R, Koduru S, Hafemann A, Hopf S, et al. Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice. Nat Med. 2016;22:1351–7.

    CAS  Article  Google Scholar 

  9. 9.

    Sehgal K, Das R, Zhang L, Verma R, Deng Y, Kocoglu M, et al. Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets. Blood. 2015;125:4042–51.

    CAS  Article  Google Scholar 

  10. 10.

    Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 2008;68:190–7.

    CAS  Article  Google Scholar 

  11. 11.

    Tanno T, Lim Y, Wang Q, Chesi M, Bergsagel PL, Matthews G, et al. Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells. Blood. 2014;123:725–33.

    CAS  Article  Google Scholar 

  12. 12.

    Spisek R, Kukreja A, Chen LC, Matthews P, Mazumder A, Vesole D, et al. Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy. J Exp Med. 2007;204:831–40.

    CAS  Article  Google Scholar 

  13. 13.

    Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S, et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature. 2013;502:65–70.

    CAS  Article  Google Scholar 

  14. 14.

    Liu Y, Huang X, He X, Zhou Y, Jiang X, Chen-Kiang S, et al. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function. FASEB J. 2015;29:4829–39.

    CAS  Article  Google Scholar 

  15. 15.

    Shi CX, Kortum KM, Zhu YX, Jedlowski P, Bruins L, Braggio E, et al. Proteasome inhibitors block Ikaros degradation by lenalidomide in multiple myeloma. Haematologica. 2015;100:e315–7.

    Article  Google Scholar 

Download references


MVD is supported in part by funds from NCI R35 CA197603, Specialized Center for Research and translational research program of Leukemia and Lymphoma Society and the Multiple Myeloma Research Foundation (MMRF). Authors would like to thank patients and clinical colleagues at Yale, and Zifeng Mai, Lin Zhang, Dr. Mehmet H Kocoglu, Carla Weibel, Jon Alderman, Grzegorz Wylezinski, Dr. Roni Nowarski for their support.

Author information




RV designed and performed experiments and wrote the manuscript. AB and KD performed clinical research and provided access to specimens. MLX provided help with immunohistochemical analyses. RAF provided access to mice used in the study. MVD provided oversight for the project and wrote manuscript. All authors contributed to interpretation of data and approved the final manuscript.

Corresponding authors

Correspondence to Rakesh Verma or Madhav V. Dhodapkar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Verma, R., Branagan, A.R., Xu, M.L. et al. Role of MBD3-SOX2 axis in residual myeloma following pomalidomide. Leukemia (2021).

Download citation


Quick links