Cereblon and Redox in Plasma Cells

The protein Cereblon (CRBN) has recently attracted considerable interest by virtue of its ability to mediate both anti-tumor as well as teratogenic activities of immunomodulatory drugs (IMiDs) ^1-3 . Certain IMiDs have been shown to re-direct CRBN-associated ubiquitylation activity towards neo-substrates such as IKZF1/3 and CK1a, thereby promoting their proteasomal degradation ^4-8. This mechanism has been implicated in the anti-proliferative effects of IMiDs in multiple myeloma (MM) and del(5q)-MDS. However, the pleiotropic anti-tumor effects of IMiDs, their adverse effects such as teratogenicity and neurotoxicity, and their synergy with proteasome inhibitors suggests further mechanisms of action. Previous research on CRBN has revealed novel insights that shed light on the physiological functions of this versatile protein in plasma cells. Indeed, next to its function as a ubiquitin ligase, CRBN has been shown to exist in ubiquitin-ligase independent complexes, where it functions as a chaperone for crucial trans-membrane receptors such as CD147 (also known as Basigin) and MCT1 (monocarboxylate transporter 1) ⁹. This functions links CRBN to the regulation of angiogenesis, cell invasion and particularly cell metabolism by governing lactate homeostasis. Likewise, CRBN has been implicated in the regulation of TrxR (thioredoxin reductase), thereby critically determining the redox balance in plasma cells ¹⁰. These findings have important implications for our understanding of IMiD biology and for the development of novel treatment approaches and predictive biomarkers for MM. Indeed, IMiDs inhibit the chaperone function of CRBN in a competitive manner and attenuate TrxR via CRBN, thereby preventing intracellular H2O2 decomposition. In turn, CRBN-dependent degradation of IKZF1 and IKZF3 have been shown to be the result high H2O2 levels. Against this background, CRBN-regulated proteins such as CD147 and MCT1 as well as TrxR may serve as new therapeutic target structures while functional read-outs as CD147 and MCT1 destabilization or antioxidative capacity may serve as predictive biomarkers for IMiD response.

1. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science . 2010;327(5971):1345- 1350.

2. 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.

3. 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.

4. Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science . 2014;343(6168):301-305.

5. Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science . 2014;343(6168):305-309.

6. 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.

7. Zhu YX, Braggio E, Shi CX, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood . 2014;124(4):536-545.

8. Kronke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature . 2015;523(7559):183-188.

9. Eichner R, Heider M, Fernandez-Saiz V, et al. Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat Med . 2016;22(7):735-743.

10. Sebastian S, Zhu YX, Braggio E, et al. Multiple myeloma cells' capacity to decompose H2O2 determines lenalidomide sensitivity. Blood . 2017;129(8):991-1007.