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Blood Cancer Discov DOI:10.1158/2643-3230.bcd-20-0105

Avadomide induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies.

Publication TypeJournal Article
Year of Publication2021
AuthorsRenneville, A, Gasser, JA, Grinshpun, DE, Beltran, PMJean, Udeshi, ND, Matyskiela, ME, Clayton, T, McConkey, M, Viswanathan, K, Tepper, A, Guirguis, AA, Sellar, RS, Cotteret, S, Marzac, C, Saada, V, De Botton, S, Kiladjian, J-J, Cayuela, J-M, Rolfe, M, Chamberlain, PP, Carr, SA, Ebert, BL
JournalBlood Cancer Discov
Volume2
Issue3
Pages250-265
Date Published2021 May
ISSN2643-3249
Abstract

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.

DOI10.1158/2643-3230.bcd-20-0105
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/34027417?dopt=Abstract

Alternate JournalBlood Cancer Discov
PubMed ID34027417
PubMed Central IDPMC8133393
Grant ListP01 CA066996 / CA / NCI NIH HHS / United States
P50 CA206963 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
R35 CA253125 / CA / NCI NIH HHS / United States