Avadomide induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies

Blood Cancer Discov. 2021 May;2(3):250-265. doi: 10.1158/2643-3230.BCD-20-0105. Epub 2021 Mar 10.


Thalidomide analogs 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.

Keywords: fusion oncoproteins; hematologic malignancies; thalidomide analogs; ubiquitination; zinc finger protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins
  • Hematologic Neoplasms* / drug therapy
  • Humans
  • Lenalidomide / pharmacology
  • Oncogene Proteins
  • Thalidomide*
  • Transcription Factors / metabolism


  • DNA-Binding Proteins
  • Oncogene Proteins
  • Transcription Factors
  • ZMYM2 protein, human
  • Thalidomide
  • Lenalidomide