ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia

Abstract

Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs1. Recognition of modified histones by “reader” proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of BET bromodomain inhibitors2, 3. We recently identified the YEATS domain as a novel acetyllysine-binding module4, yet its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralog AF9, is required for disease maintenance in acute myeloid leukaemia (AML). CRISPR-Cas9 mediated depletion of ENL led to anti-leukemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and ChIP-seq analyses revealed that ENL binds to acetylated histone H3, and colocalizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemias. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced RNA polymerase II recruitment to ENL target genes, leading to suppression of oncogenic gene expression programs. Importantly, disruption of ENL’s functionality further sensitized leukaemia cells to BET inhibitors. Together, our study identifies ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in AML and suggests that displacement of ENL from chromatin may be a promising epigenetic therapy alone or in combination with BET inhibitors for AML.

Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy

“…Mutations that stabilize SEC lead to the developmental syndrome CHOPS (Izumi et al, 2015). SEC is a regulatory factor of MYC (Erb et al, 2017; Luo et al, 2012a; Takahashi et al, 2011; Wan et al, 2017), which is a master regulator for cancer cell proliferation and contributes to the pathogenesis of a majority of human cancers by coordinated amplification of transcription (Lin et al, 2012; Nie et al, 2012; Sabo et al, 2014; Walz et al, 2014), and is particularly required for expression of cell division and pre-mRNA splicing factors (Hsu et al, 2015; Koh et al, 2015). Given the importance of transcription elongation control in cancer pathogenesis and the paradigm of BET domain inhibitors in targeting MYC expression and the transcriptional elongation misregulation in cancers (Bradner et al, 2017), developing inhibitors of SEC can serve as a tool for both mechanistic studies of SEC and for cancer therapeutics.…”

A New Complex Karyotype Involving a <b><i>KMT2A</i></b>-r Variant Three-Way Translocation in a Rare Clinical Presentation of a Pediatric Patient with Acute Myeloid Leukemia

“…The regulation mechanism consists of the binding of MLLT1 to acetylated histone H3 on promoters that are actively transcribed during the leukemia process. In addition, bromodomain and extra-terminal (BET) inhibitors, which block ligation between BET proteins and acetylated histones as well as transcription factors, might be a therapeutic option for inhibiting MLLT1 ligation to chromatin [Wan et al, 2017].…”

Small Molecules and Their Role in Effective Preclinical Target Validation

“…Using CRISPR-Cas9 gene editing and a targeted PROTAC approach, ENL was identified as an oncogenic transcription regulator involved in acute myeloid leukemia. ENL displacement from chromatin was shown, with in vitro and in vivo evidence, to reduce oncogenic gene expression while simultaneously sensitizing leukemia cells to BET inhibitors, presenting a promising standalone epigenetic therapy for acute myeloid leukemia, or as a combination therapy with BET inhibitors [18,19]. In addition to target-specific modulation, small molecules can also be used as technology facilitators, and in the context of target validation it should be noted that CRISPR often uses small molecule enhancers to improve efficiency and precision [20].…”