| Autor: |
Andrew A Guirguis, Benjamin L. Ebert, Sophie Cotteret, Marie McConkey, Rob S. Sellar, Mary E Matyskiela, Jessica A. Gasser, Christophe Marzac, Aline Renneville, Steven A. Carr, Alexander Tepper, Mark Rolfe, Namrata D. Udeshi, Kaushik Viswanathan, Stéphane de Botton, Thomas Clayton, Jean-Michel Cayuela, Philip P Chamberlain, Véronique Saada, Jean-Jacques Kiladjian, Pierre M. Jean Beltran, Daniel E Grinshpun |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Blood Cancer Discov |
| ISSN: |
2643-3249 |
| Popis: |
Thalidomide analogues exert their therapeutic effects by binding to the CRL4CRBN E3 ubiquitin ligase, promoting ubiquitination and subsequent proteasomal degradation of specific protein substrates. Drug-induced degradation of IKZF1 and IKZF3 in B-cell malignancies demonstrates the clinical utility of targeting disease-relevant transcription factors for degradation. Here, we found that avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 (ZNF198), a transcription factor involved in balanced chromosomal rearrangements with FGFR1 and FLT3 in aggressive forms of hematologic malignancies. The minimal drug-responsive element of ZMYM2 is a zinc-chelating MYM domain and is contained in the N-terminal portion of ZMYM2 that is universally included in the derived fusion proteins. We demonstrate that avadomide has the ability to induce proteasomal degradation of ZMYM2–FGFR1 and ZMYM2–FLT3 chimeric oncoproteins, both in vitro and in vivo. Our findings suggest that patients with hematologic malignancies harboring these ZMYM2 fusion proteins may benefit from avadomide treatment. Significance: We extend the potential clinical scope of thalidomide analogues by the identification of a novel avadomide-dependent CRL4CRBN substrate, ZMYM2. Avadomide induces ubiquitination and degradation of ZMYM2–FGFR1 and ZMYM2–FLT3, two chimeric oncoproteins involved in hematologic malignancies, providing a proof of concept for drug-induced degradation of transcription factor fusion proteins by thalidomide analogues. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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