RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

By J. Zuber, Junwei Shi, E. Wang, Amy R. Rappaport, H. Herrmann, E. Sison, D. Magoon, J. Qi, Katharina Blatt, M. Wunderlich and 10 more. Nature, 2011

1,853 citations recorded by the source corpus.

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e01502b7471af390a94b9c48a1a14b3fb0b0da35

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Citations in the corpus

A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “Most recently, translocations and/or overexpression of the bromodomain protein BRD4 have been linked to a driver role in a lethal form of paediatric epithelial cancer and to AM”
Cancer epigenetics: from mechanism to therapy. (2012, background): “…the expression of MYC was noted to be substantially decreased in a variety of malignant hematopoietic cell lines, including MLL-translocated acute myeloid leukemia (Dawson et al., 2011; Zuber et al., 2011), multiple myeloma (Delmore et al., 2011), and Burkitt's lymphoma (Mertz et al., 2011).”
The mechanisms behind the therapeutic activity of BET bromodomain inhibition (2014, background): “…BCL2 from a heterologous promoter can partially alleviate the anticancer effects of JQ1/I-BET, highlighting that suppression of these genes is an important downstream effect of BET inhibition in these malignancies (Dawson et al., 2011; Delmore et al., 2011; Mertz et al., 2011; Zuber et al., 2011).”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “Guadecitabine (SGI-110), a second-generation DNMT inhibitor, acts as a prodrug of decitabine, conferring better stability and reduced toxicity in tumor-infected nude mice compared to decitabine (Yoo et al., 2007; Chuang et al., 2010), and it has been tested in phase II clinical trials for the treatm”
Transcriptional Addiction in Cancer (2017, positive): “The MLL-AF fusions thus recruit DOT1L to MLL-target genes, including the TF genes HOXA9 and MEIS1, and the hypermethylation of histones leads to aberrant expression of those genes, which in turn drive leukemogenesis (Figure 6C) (Chen and Armstrong, 2015).”
Discovery and Characterization of Super-Enhancer Associated Dependencies in Diffuse Large B-Cell Lymphoma (2013, positive): “…has recently identified a role for BET bromodomains in supporting the transcription of known DLBCL oncogenes (MYC and BCL2) in studies of acute leukemia, multiple myeloma and Burkitt lymphoma (Dawson et al., 2011; Delmore et al., 2011; Mertz et al., 2011; Ott et al., 2012; Zuber et al., 2011).”
A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia (2016, background): “, 2011), and both a mechanistic and an RNAi-based epigenetics-focused screen identified BRD4 as a therapeutic target against AMLs of different genotypes (Dawson et al., 2011; Zuber et al., 2011).”