Transcriptional Plasticity Drives IMiD and p300 Inhibitor Resistance in Multiple Myeloma

Abstract

In this issue of Blood Cancer Discovery, Neri, Barwick, and colleagues and Welsh, Barwick, and colleagues performed RNA sequencing, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and genetic studies to characterize the underlying mechanisms of immunomodulatory drug (IMiD) resistance in multiple myeloma. They demonstrated that IMiD resistance is driven by sustained expression of MYC and IRF4 via transcriptional plasticity that involves induction of ETV4 and BATF proteins, the binding of these proteins to their super-enhancers, and the recruitment of BRD4 and p300. Finally, these studies suggest IMiD and p300 inhibitor combination as a promising therapeutic strategy in multiple myeloma. See related article by Neri, Barwick, et al., p. 56 (9). See related article by Welsh, Barwick, et al., p. 34 (10).

Figure 1.

Transcriptional plasticity sustains SE activities that drive MYC-IRF4-dependent IMiD resistance in multiple myeloma (MM). IMiDs induce multiple myeloma cell death by promoting CRBN-mediated downregulation of IKZF1/IKZF3 and subsequent downregulation of MYC and IRF4 transcription. In IMiD-resistant multiple myeloma cells, IKZF1/IKZF3 dependence of MYC and IRF4 transcription is circumvented via transcriptional plasticity that involves the induction of ETV4 and BATF transcription factors, which bind and recruit p300 to MYC and IRF4 super-enhancers. Accordingly, p300i potentiates the efficacy of IMiDs by downregulating IRF4 and MYC transcription in IMiD-resistant multiple myeloma cells. Figure concept and design by Ben Barwick.