Abstract
BET inhibitor–resistant cells undergo transcriptional rewiring to reactivate MYC gene expression.
Major finding: BET inhibitor–resistant cells undergo transcriptional rewiring to reactivate MYC gene expression.
Mechanism: Compensatory activation of WNT/β-catenin binding at MYC enhancer regions drives resistance.
Impact: WNT pathway activation may represent a predictive biomarker of BET inhibitor response in AML.
Epigenetic regulators, such as the bromodomain and extra terminal (BET) family of proteins, have been increasingly implicated in cancer initiation and maintenance, and have led to the development of small-molecule inhibitors targeting the BET domain, such as I-BET and JQ1. Although BET inhibitors have shown early success in acute myeloid leukemia (AML), little is known about the underlying molecular mechanisms that govern resistance to BET inhibition. To address this question, Fong and colleagues generated a model of BET inhibitor resistance using MLL–AF9-expressing primary murine hematopoietic stem and progenitor cells treated with I-BET. I-BET–resistant cells were characterized by decreased expression of the lineage markers GR1 and CD11B and were enriched for leukemia stem cells in limiting-dilution experiments. Although I-BET–resistant cells shared few genetic aberrations, transcriptional profiling revealed increased expression of the BRD4 target gene MYC, despite an overall decrease in BRD4 chromatin binding, and enhanced activation of the WNT transcriptional program. Mechanistically, β-catenin replaced BRD4 at MYC regulatory sequences to drive increased MYC expression in I-BET–resistant cells. In a second report, Rathert, Roth, and colleagues revealed through an RNAi screen that suppression of the polycomb repressive complex 2 subunit SUZ12 promotes JQ1 resistance in a BET inhibitor–sensitive AML mouse model. Under long-term JQ1 treatment, SUZ12-deficient AML cells restored transcription of BRD4-dependent genes such as MYC through an adaptation process involving the remodeling of enhancer landscapes and the activation of WNT signaling. In line with this result, JQ1-resistant human leukemia cell lines and primary samples displayed similar MYC enhancer profiles and an increased expression of genes associated with WNT signaling. Suppression of WNT targets resensitized cells to JQ1 in vitro, whereas WNT activation drove de novo JQ1 resistance in vivo. Together, these data suggest that compensatory activation of transcriptional pathways, such as WNT–MYC, may underlie BET inhibitor resistance in AML.
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