Issues

Immunomodulatory imide drugs (IMiD) are potent antimyeloma therapeutics degrading IKZF1/3 transcription factors. Two studies in the current issue unravel transcriptional mechanisms of IMiD action and resistance. Welsh, Barwick et al. (p. 34) identify the role of IKZF1/3 in cooperation with EP300 and BRD4 at super-enhancers of IRF4 and MYC as the key to antimyeloma IMiD activity, which can be further potentiated by coinhibition of EP300. Despite continued IKZF1/3 degradation, resistance to IMiD can arise via increased BATF binding at these super-enhancers. In a complementary study, Neri, Barwick et al. (p. 56) reveal another IMiD resistance pathway where ETV4 steps in place of IKZF1/3 to retain EP300 and BRD4 at the oncogenic super-enhancers. The findings, placed in the Spotlight by Yun and Cleveland (p. 5), highlight the critical role of transcriptional regulation in IMiD effectiveness and resistance and point to new strategies for maximizing IMiD efficacy in myeloma therapy.