Avadomide induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Thalidomide analogs target CRL4^CRBN E3 ubiquitin ligase for protein degradation.
• Degradation of IKZF1 and IKZF3 by drugs in B-cell malignancies shows clinical utility.
• ZMYM2 (ZNF198) is a transcription factor involved in aggressive hematologic malignancies via chromosomal rearrangements.

Purpose of the Study:

• To investigate avadomide's effect on ZMYM2 degradation.
• To identify the drug-responsive element in ZMYM2.
• To assess avadomide's efficacy against ZMYM2 fusion oncoproteins.

Main Methods:

• CRBN-dependent ubiquitination assays.
• Proteasomal degradation studies in vitro and in vivo.
• Analysis of ZMYM2 N-terminal domain and MYM domain function.

Main Results:

• Avadomide induces CRBN-dependent ubiquitination and degradation of ZMYM2.
• The minimal drug-responsive element is the zinc-chelating MYM domain in the N-terminus.
• Avadomide degrades ZMYM2-FGFR1 and ZMYM2-FLT3 oncoproteins.

Conclusions:

• Avadomide targets ZMYM2 for proteasomal degradation.
• ZMYM2 fusion proteins in hematologic malignancies are susceptible to avadomide.
• Patients with ZMYM2 fusion-positive malignancies may benefit from avadomide therapy.