Avadomide induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies

Thalidomide analogs exert their therapeutic effects by binding to the CRL4 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 targ...

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Published in:Blood cancer discovery 2021-05, Vol.2 (3), p.250-265
Main Authors: Renneville, Aline, Gasser, Jessica A, Grinshpun, Daniel E, Jean Beltran, Pierre M, Udeshi, Namrata D, Matyskiela, Mary E, Clayton, Thomas, McConkey, Marie, Viswanathan, Kaushik, Tepper, Alexander, Guirguis, Andrew A, Sellar, Rob S, Cotteret, Sophie, Marzac, Christophe, Saada, Véronique, De Botton, Stéphane, Kiladjian, Jean-Jacques, Cayuela, Jean-Michel, Rolfe, Mark, Chamberlain, Philip P, Carr, Steven A, Ebert, Benjamin L
Format: Article
Language:English
Subjects:
DNA-Binding Proteins
Hematologic Neoplasms - drug therapy
Humans
Lenalidomide - pharmacology
Life Sciences
Oncogene Proteins
Thalidomide
Transcription Factors - metabolism
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Summary:Thalidomide analogs exert their therapeutic effects by binding to the CRL4 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 and 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 and . Our findings suggest that patients with hematologic malignancies harboring these fusion proteins may benefit from avadomide treatment.
ISSN:2643-3230
2643-3249
DOI:10.1158/2643-3230.bcd-20-0105