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The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [RNA-Seq II]

ABSTRACT: The histone acetylation reader ENL is identifed as a key factor controlling super-enhancer-driven transcription. We thus perturbed BRD4, a well-known super-enhancer regulator, protein expression with a well-validated BRD4 PROTAC (proteolysis targeting chimeric) compound dBET1 and examined whether BRD4 was required for proper function of ENL in regulation gene transcription.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249552 | GEO | 2024/01/18

REPOSITORIES: GEO

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The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [RNA-seq]

Project description:The histone acetylation reader ENL is identifed as a key factor controlling super-enhancer-driven transcription. Therefore, we constructed a targeted degradation system of endogenous ENL protein and investigated the roles of ENL in regulating oncogenic transcription through epigenetic reprogramming.

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A potent and selective small-molecule degrader of ENL suppresses leukemia progression in vivo (RNA-Seq)

Project description:ENL, a stoichiometric component of the Super Elongation Complex (SEC) as well as the histone H3K79 methyltransferase DOT1L complex, is involved in the regulation of transcription elongation. Loss-of-function studies of ENL highlighted an essential role for its chromatin reader YEATS domain in the progression of acute leukemia, suggesting ENL as an attractive therapeutic target for leukemia therapy. Proteolysis targeting chimeras (PROTACs), a class of new therapeutic modalities, have the potential to degrade target proteinsthrough the ubiquitin-proteasome system. PROTACs have the potential to deliver robust therapeutic effects at low doses and infrequent dosing regimens with less side-effects. Here, we designed and synthesized a serial of ENL PROTACs. Through screening by ENL degradation in human leukemia cells, we identified MS47 as a potent ENL PROTAC. MS47 efficiently and specifically degrades ENL in a concentration-dependent and time dependent manner. In line with the mechanism of action of PROTACs, proteasome inhibitors can block ENL degradation mediated by MS47. MS47 suppresses survival and growth of a panel of acute leukemia cells, and efficiently suppresses the expression of ENL target genes, including Hoxa9, Meis1, Myb and Myc. In disseminated xenograft model, MS47 significantly benefits mouse survival, inhibits leukemia cell growth in vivo. No obvious toxic effect shown in toxicity test in vivo. Modest changes occurred on normal hematopoiesis. Together, our study developed a potent ENL PROTAC for leukemia treatment.

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The histone acetylation reader ENL is required for oncogenic transcription driven by super-enhancer and represents a synergistic vulnerability for BET inhibition [RNA-Seq II]

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