ORCID Profile
0000-0003-0805-9640
Current Organisations
University of Lille
,
Gustave Roussy
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Publisher: Springer Science and Business Media LLC
Date: 13-07-2017
DOI: 10.1038/LEU.2017.213
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.C.6550374
Abstract: Abstract Thalidomide analogues exert their therapeutic effects by binding to the CRL4 sup CRBN /sup 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 i FGFR1 /i and i FLT3 /i 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 i in vitro /i and i in vivo /i . Our findings suggest that patients with hematologic malignancies harboring these i ZMYM2 /i 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 CRL4 sup CRBN /sup 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. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22543713
Abstract: Supplementary Methods, Figures, and Tables
Publisher: Springer Science and Business Media LLC
Date: 26-02-2018
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22543713.V1
Abstract: Supplementary Methods, Figures, and Tables
Publisher: American Association for Cancer Research (AACR)
Date: 10-03-2021
DOI: 10.1158/2643-3230.BCD-20-0105
Abstract: 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.
Publisher: Elsevier BV
Date: 08-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22543710.V1
Abstract: Supplementary Table 1. Proteomic data
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.C.6550374.V1
Abstract: Abstract Thalidomide analogues exert their therapeutic effects by binding to the CRL4 sup CRBN /sup 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 i FGFR1 /i and i FLT3 /i 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 i in vitro /i and i in vivo /i . Our findings suggest that patients with hematologic malignancies harboring these i ZMYM2 /i 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 CRL4 sup CRBN /sup 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. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2643-3230.22543710
Abstract: Supplementary Table 1. Proteomic data
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-11-2018
Abstract: Thalidomide and its analogs improve the survival of patients with multiple myeloma and other blood cancers. Previous work showed that the drugs bind to the E3 ubiquitin ligase Cereblon, which then targets for degradation two specific zinc finger (ZF) transcription factors with a role in cancer development. Sievers et al. found that more ZF proteins than anticipated are destabilized by thalidomide analogs. A proof-of-concept experiment revealed that chemical modifications of thalidomide can lead to selective degradation of specific ZF proteins. The detailed information provided by structural, biochemical, and computational analyses could guide the development of drugs that target ZF transcription factors implicated in human disease. Science , this issue p. eaat0572
No related grants have been discovered for ALINE RENNEVILLE.