#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Cereblon –  a New Target of Therapy in the Treatment of Multiple Myeloma


Authors: M. Staňková 1;  L. Bešše 1,2;  L. Sedlaříková 1,2;  D. Vrábel 1;  R. Hájek 1,2;  S. Ševčíková 1,2
Authors‘ workplace: Babákova myelomová skupina, Ústav patologické fyziologie, LF MU, Brno 1;  Oddělení klinické hematologie, FN Brno 2
Published in: Klin Onkol 2014; 27(5): 326-330
Category: Reviews
doi: https://doi.org/10.14735/amko2014326

Overview

Treatment of multiple myeloma (MM), currently an incurable disease, aims to achieve complete remission. Immunomodulatory drugs (IMiDs), represented by thalidomide, are one class of very effective drugs. However, the mechanism of IMiDs action is not yet completely understood. Recent research suggests that cereblon (CRBN) plays an important role in mediating anti-tumor effects of IMiDs; therefore, our review focuses on this protein. CRBN is a substrate receptor of Cul4- E3 ubiquitin ligase complex, and thus recognizes proteins destined for degradation. Bind­ing of CRBN and IMiDs inhibits function of the entire ubiquitin proteasome complex which partly explains their anti-tumor effects. In addition, a correlation between CRBN gene expres­sion and effectiveness of treatment in MM patients treated with IMiDs was confirmed. These findings suggest that CRBN expression could possibly serve as a bio­marker to predict response to IMiD in MM patients.

Key words:
cereblon – multiple myeloma –  immunomodulatory drugs

This study was supported by grants IGA MZ CR NT14575 and NT12130.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
12. 5. 2014

Accepted:
19. 5. 2014


Sources

1. Harris NL, Jaffe ES, Diebold J et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol 1999; 10(12): 1419–1432.

2. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple mye­loma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003; 121(5): 749–757.

3. Hájek R, Adam Z, Ščudla V et al. Dia­gnostika a léčba mnohočetného myelomu. Tranfuze a hematologie dnes 2012; 18 (Suppl 1): 1–89.

4. Sedlaříková L, Kubiczková L, Ševčíková S et al. Mechanism of immunomodulatory drugs in multiple myeloma. Leuk Res 2012; 36(10): 1218–1224. doi: 10.1016/j.leuk­res.2012.05.010.

5. Ito T, Ando H, Suzuki T et al. Identification of a primary target of thalidomide teratogenicity. Science 2010; 327(5971): 1345–1350. doi: 10.1126/science.1177319.

6. Ohta T, Michel JJ, Schottelius AJ et al. ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell 1999; 3(4): 535–541.

7. Shiyanov P, Nag A, Raychaudhuri P. Cullin 4A associates with the UV‑ damaged DNA‑binding Protein DDB. J Biol Chem 1999; 274(50): 35309–35312.

8. Heintel D, Rocci A, Ludwig H et al. High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br J Haematol 2013; 161(5): 695–700. doi: 10.1111/bjh.12338.

9. Broyl A, Kuiper R, van Duin M et al. High cereblon expression is associated with better survival in patients with newly dia­gnosed multiple myeloma treated with thalidomide maintenance. Blood 2013; 121(4): 624–627. doi: 10.1182/blood‑2012‑06‑438101.

10. Schuster SR, Kortuem KM, Zhu YX et al. The clinical significance of cereblon expression in multiple mye­loma. Leuk Res 2014; 38(1): 23–28. doi: 10.1016/j.leuk­res.2013.08.015.

11. Jo S, Lee KH, Song S et al. Identification and functional characterization of cereblon as a binding protein for large‑conductance calcium‑activated potassium channel in rat brain. J Neurochem 2005; 94(5): 1212–1224.

12. Higgins JJ, Rosen DR, Loveless JM et al. A gene for nonsyndromic mental retardation maps to chromosome 3p25- pter. Neurology 2000; 55(3): 335–340.

13. Higgins JJ, Pucilowska J, Lombardi RQ et al. A mutation in a novel ATP‑dependent Lon protease gene in a kindred with mild mental retardation. Neurology 2004; 63(10): 1927–1931.

14. Aizawa M, Abe Y, Ito T et al. mRNA distribution of the thalidomide binding protein cereblon in adult mouse brain. Neurosci Res 2011; 69(4): 343–347. doi: 10.1016/j.neures.2010.12.019.

15. Higgins JJ, Tal AL, Sun X et al. Temporal and spatial mouse brain expression of cereblon, an ionic channel regulator involved in human intelligence. J Neurogenet 2010; 24(1): 18–26. doi: 10.3109/01677060903567849.

16. Hohberger B, Enz R. Cereblon is expressed in the retina and binds to voltage‑gated chloride channels. FEBS Lett 2009; 583(4): 633–637. doi: 10.1016/j.febslet.2009.01.018.

17. Xin W, Xiaohua N, Peilin C et al. Primary function analysis of human mental retardation related gene CRBN. Mol Biol Rep 2008; 35(2): 251–256.

18. Lee KM, Jo S, Kim H et al. Functional modulation of AMP‑activated protein kinase by cereblon. Biochim Biophys Acta 2011; 1813(3): 448–455. doi: 10.1016/j.bbamcr.2011.01.005.

19. Lee KM, Lee J, Park CS. Cereblon inhibits proteasome activity by binding to the 20S core proteasome subunit beta type 4. Biochem Biophys Res Commun 2012; 427(3): 618–622. doi: 10.1016/j.bbrc.2012.09.108.

20. Hershko A, Heller H, Elias S et al. Components of ubiquitin‑protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem 1983; 258(13): 8206–8214.

21. Bedewy AM, EL‑ Maghraby SM. Do baseline Cereblon gene expression and IL‑6 receptor expression determine the response to thalidomide‑dexamethasone treatment in multiple myeloma patients? Eur J Haematol 2014; 92(1): 13–18. doi: 10.1111/ejh.12207.

22. Zhu YX, Braggio E, Shi CX et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011; 118(18): 4771–4779. doi: 10.1182/blood‑2011‑05‑356063.

23. Gandhi AK, Mendy D, Waldman M et al. Measuring cereblon as a bio­marker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity. Br J Haematol 2014; 164(2): 233–244. doi: 10.1111/bjh.12622.

24. Thakurta A, Gandhi AK, Waldman MF et al. Absence of mutations in cereblon (CRBN) and DNA damage‑binding protein 1 (DDB1) genes and significance for IMiD therapy. Leukemia 2014; 28(5): 1129–1131. doi: 10.1038/leu.2013.315.

25. Egan JB, Kortuem KM, Kurdoglu A et al. Extramedullary myeloma whole genome sequencing reveals novel mutations in Cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease. Br J Haematol 2013; 161(5): 748–751. doi: 10.1111/bjh.12291.

26. Gandhi AK, Kang J, Havens CG 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(6): 811–821. doi: 10.1111/bjh.12708.

27. Bandyopadhyay S, Duré M, Paroder M et al. Interleukin 2gene transcription is regulated by Ikaros‑induced changes in histone acetylation in anergic T cells. Blood 2007; 109(7): 2878–2886.

28. Shaffer AL, Emre NC, Lamy L et al. IRF4 addiction in multiple myeloma. Nature 2008; 454(7201): 226–231. doi: 10.1038/nature07064.

29. Lopez‑ Girona A, Mendy D, Ito T et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 2012; 26(11): 2326–2335. doi: 10.1038/leu.2012.119.

Labels
Paediatric clinical oncology Surgery Clinical oncology
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#