Tumor-intrinsic MLL1 drives transcriptional reprogramming in response to EZH2 inhibition.
Major finding: Tumor-intrinsic MLL1 drives transcriptional reprogramming in response to EZH2 inhibition.
Mechanism: MLL1 interacts with the p300/CBP complex to drive reciprocal H3K27ac gain at sites of H3K27me loss.
Impact: MLL1 status may inform precision therapy for patients with EZH2-overexpressing tumors.
Overexpression or gain-of-function mutations in EZH2, the enzymatic subunit of the histone methyltransferase polycomb repressive complex 2 (PRC2), promote oncogenesis in solid tumors and hematologic malignancies, respectively. Given that mutant EZH2 has been shown to drive H3K27 methylation (H3K27me)–dependent growth, Huang, Yan, Zhang, Wang, and colleagues epigenetically profiled a panel of EZH2-overexpressing blood and solid cancer cell lines with varying sensitivities to EZH2 inhibition (EZH2i). EZH2i reduced H3K27me in both hematologic and solid-cancer cell lines, inhibited growth of hematologic cancer cell lines, and induced H3K27 acetylation (H3K27ac) in EZH2i-resistant cell lines. Knockdown of p300 or CBP, both of which comprise the complex that catalyzes H3K27ac, sensitized EZH2i-resistant cell lines that express MLL1, which facilitates binding of p300/CBP to target sites, to EZH2 inhibition. Consistent with these findings, MLL1 expression was correlated with increased H3K27ac in EZH2i-resistant cell lines, and ablation of MLL1 resulted in decreased formation of p300/CBP complexes and H3K27ac. Integrated chromatin immunoprecipitation sequencing, RNA sequencing, and proteomic analysis showed that EZH2i treatment induced transcriptional reprogramming via a H3K27me-to-H3K27ac switch in EZH2i resistant cell lines. Treatment with a BRD4 inhibitor, which targets H3K27ac, sensitized EZH2i-resistant cells to EZH2 inhibition in vitro, and combined inhibition of BRD4 and EZH2 reduced growth of a subset of patient-derived xenografts (PDX) in vivo. Proteomic analyses revealed that PDXs that did not respond to combined inhibition of BRD4 and EZH2 exhibited increased MAPK signaling due to BRD4i-mediated inactivation of ERK1 and subsequent activation of ERK2. Combined targeting of EZH2, BRD4, and ERK1/2 suppressed the growth of liver and pancreatic cancer xenografts without significant toxicity in vivo. These results show that resistance to EZH2 inhibition is driven by MLL1-mediated transcriptional reprogramming in patients with EZH2-overexpressing tumors, who potentially could be stratified by MLL1 status for EZH2i either as a monotherapy or in combination with therapies targeting H3K27ac and/or MAPK signaling.
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