Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiDs). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma

“…Our data suggest that it is more complex, and we cannot rule out a model whereby transcription factor combinations such as IKZF1 and ETV4 are required to maintain a threshold level of enhancer activity to maintain oncogene expression and MM survival. Additionally, previous studies ( 36 ) and those in the companion paper from Welsh and colleagues ( 49 ) found that ectopic MYC expression failed to rescue MM cells from IMiD treatment, suggesting that MYC is not the only determinant of IMiD responses. Similarly, it is possible that MYC regulates IKZF1 and IKZF3 expression, and as such MYC downregulation would further potentiate IMiD responses.…”

“…This is supported by recent reports that P300 disruption effectively targets MM and other hematologic malignancies ( 50, 51 ). Indeed, in a study by Welsh and colleagues ( 49 ) IMiDs are shown to synergize with P300 inhibitors, and such rational combinations may be critical for overcoming IMiD resistance in MM.…”

Cardiovascular Alterations in Workers Performing at High Altitude on the Etna Volcano

“…However, some people react abnormally to high altitude, experiencing a significant increase in blood pressure. Unfortunately, there is currently no method to identify these people in advance before climbing to high altitudes [19].…”