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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.).

Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, Ito T, Ando H, Waldman MF, Thakurta A, Klippel A, Handa H, Daniel TO, Schafer PH, Chopra R - Br. J. Haematol. (2013)

Bottom Line: 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.In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4(CRBN) , leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.

View Article: PubMed Central - PubMed

Affiliation: Celgene Corporation, Summit, NJ, USA.

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Dose-dependent Aiolos inhibition in peripheral T cells from healthy volunteers administered with lenalidomide. Healthy volunteers were administered either placebo, 10 or 50 mg of lenalidomide and blood was drawn 6 h post-dose. Aiolos levels were measured in CD3+ T cells by flow cytometry (n = 5–8 for each treatment arm). MEFL, mean equivalent fluorochrome labelling; SEM, standard error of the mean.
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fig08: Dose-dependent Aiolos inhibition in peripheral T cells from healthy volunteers administered with lenalidomide. Healthy volunteers were administered either placebo, 10 or 50 mg of lenalidomide and blood was drawn 6 h post-dose. Aiolos levels were measured in CD3+ T cells by flow cytometry (n = 5–8 for each treatment arm). MEFL, mean equivalent fluorochrome labelling; SEM, standard error of the mean.

Mentions: Healthy volunteers were administered either placebo or lenalidomide at doses of 10 or 50 mg. Blood samples were drawn immediately prior to dosing (pre-dose) and 6 h post-single dose of placebo or lenalidomide. Peripheral blood mononuclear cells were isolated by Ficoll from whole blood samples and viably frozen in DMSO prior to flow cytometric analysis of Aiolos expression. Our results indicate that Aiolos expression in peripheral T cells was reduced by 18% and 32% upon administration of 10 or 50 mg lenalidomide, respectively (Fig 8). Therefore, the effects of lenalidomide on Aiolos protein levels observed in vitro were also detected in human volunteers, suggesting that the measurement of Aiolos protein levels in peripheral blood cells can be used as a clinical biomarker of lenalidomide activity and may be used to define the dose and schedule for novel indications and next-generation compounds.


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.).

Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, Ito T, Ando H, Waldman MF, Thakurta A, Klippel A, Handa H, Daniel TO, Schafer PH, Chopra R - Br. J. Haematol. (2013)

Dose-dependent Aiolos inhibition in peripheral T cells from healthy volunteers administered with lenalidomide. Healthy volunteers were administered either placebo, 10 or 50 mg of lenalidomide and blood was drawn 6 h post-dose. Aiolos levels were measured in CD3+ T cells by flow cytometry (n = 5–8 for each treatment arm). MEFL, mean equivalent fluorochrome labelling; SEM, standard error of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232904&req=5

fig08: Dose-dependent Aiolos inhibition in peripheral T cells from healthy volunteers administered with lenalidomide. Healthy volunteers were administered either placebo, 10 or 50 mg of lenalidomide and blood was drawn 6 h post-dose. Aiolos levels were measured in CD3+ T cells by flow cytometry (n = 5–8 for each treatment arm). MEFL, mean equivalent fluorochrome labelling; SEM, standard error of the mean.
Mentions: Healthy volunteers were administered either placebo or lenalidomide at doses of 10 or 50 mg. Blood samples were drawn immediately prior to dosing (pre-dose) and 6 h post-single dose of placebo or lenalidomide. Peripheral blood mononuclear cells were isolated by Ficoll from whole blood samples and viably frozen in DMSO prior to flow cytometric analysis of Aiolos expression. Our results indicate that Aiolos expression in peripheral T cells was reduced by 18% and 32% upon administration of 10 or 50 mg lenalidomide, respectively (Fig 8). Therefore, the effects of lenalidomide on Aiolos protein levels observed in vitro were also detected in human volunteers, suggesting that the measurement of Aiolos protein levels in peripheral blood cells can be used as a clinical biomarker of lenalidomide activity and may be used to define the dose and schedule for novel indications and next-generation compounds.

Bottom Line: 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.In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4(CRBN) , leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.

View Article: PubMed Central - PubMed

Affiliation: Celgene Corporation, Summit, NJ, USA.

Show MeSH