Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies

Abstract

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