CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL
| Autor: | Patrick Hagner, Jolanta Kosek, Michael Pourdehnad, Jian Kang, Hon-Wah Man, Peter H. Schafer, Courtney G. Havens, Rama K. Narla, Anita Gandhi, Emily Rychak, Anjan Thakurta, Anke Klippel, Celia Fontanillo, Antonia Lopez-Girona, Leo Barnes, Hsiling Chiu, Gang Lu, Matthew Trotter, Michelle Waldman, Chad C. Bjorklund, Heather Raymon, Michael D. Amantangelo, Rajesh Chopra, Thomas O. Daniel, Gody Khambatta, Ti Cai, Suzana Couto, Maria Wang, Mike Breider |
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| Rok vydání: | 2015 |
| Předmět: |
Interferon Regulatory Factor-7
T-Lymphocytes Ubiquitin-Protein Ligases Immunology Antineoplastic Agents Mice SCID Biochemistry Ikaros Transcription Factor Mice Interferon Cell Line Tumor medicine Animals Humans RNA Small Interfering Transcription factor Lenalidomide Piperidones Adaptor Proteins Signal Transducing Quinazolinones B-Lymphocytes biology Cereblon Lentivirus Molecular Mimicry Germinal center Cell Biology Hematology Xenograft Model Antitumor Assays Ubiquitin ligase Thalidomide Gene Expression Regulation Neoplastic Proteolysis biology.protein Cancer research Interferons Lymphoma Large B-Cell Diffuse Signal transduction Cullin medicine.drug Peptide Hydrolases Signal Transduction |
| Zdroj: | Blood. 126(6) |
| ISSN: | 1528-0020 |
| Popis: | Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)-stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines. Our results provide mechanistic insight into the cell-of-origin independent antilymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide. |
| Databáze: | OpenAIRE |
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