Fig. 8: A tentative enhancer remodeling model to explain the synergistic effect of BETi and THZ1 on BETi-resistant leukemia. | Nature Communications

Fig. 8: A tentative enhancer remodeling model to explain the synergistic effect of BETi and THZ1 on BETi-resistant leukemia.

From: A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells

Fig. 8

MYC expression is regulated by the classic super-enhancer BENC (E1-E5) in BETi-sensitive leukemia cells, which is mediated by BRD4 binding. BETi blocks the BRD4 binding to its genomic targets and subsequently inhibits the expression of MYC and cell growth. Long-term drug treatment or primary resistance may restore MYC expression by enhancer remodeling: PVT1 acts as a de novo BRD4 binding-independent enhancer, which can recruit other transcription factors and RNA Polymerase II (Pol II) to the MYC promoter and initiate MYC expression. THZ1 treatment reduces the Pol II occupancy to suppress the re-activated MYC transcription.

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