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 CRL4CRBN. (13th December 2013)

• Record Type: Journal Article
• Authors: Gandhi, Anita K.; Kang, Jian; Havens, Courtney G.; Conklin, Thomas; Ning, Yuhong; Wu, Lei; Ito, Takumi; Ando, Hideki; Waldman, Michelle F.; Thakurta, Anjan; Klippel, Anke; Handa, Hiroshi; Daniel, Thomas O.; Schafer, Peter H.; Chopra, Rajesh
• Is Part Of: British journal of haematology. Volume 164:Number 6(2014:Mar.)
• Page Start: 811
• Page End: 821
• Publication Date: 2013-12-13
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.12708
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh12708-abs-0001"> <title>Summary</title> <p>Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4<sup>CRBN</sup>. T cell co‐stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4<sup>CRBN</sup> substrates responsible for T cell co‐stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the <italic>IKZF1</italic> gene) and Aiolos (IKZF3, encoded by the <italic>IKZF3</italic> gene) with CRL4<sup>CRBN</sup> is induced by lenalidomide or pomalidomide. Each agent promotes Aiolos and Ikaros binding to CRL4<sup>CRBN</sup> with enhanced ubiquitination leading to cereblon‐dependent proteosomal degradation in T lymphocytes. We confirm that Aiolos and Ikaros are transcriptional repressors of interleukin‐2 expression. The findings link lenalidomide‐ or pomalidomide‐induced degradation of these transcriptional suppressors to well documented T cell activation. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated Aiolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4<sup>CRBN</sup>, leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.</p> </abstract>