Applying 89Zr-Transferrin To Study the Pharmacology of Inhibitors to BET Bromodomain Containing Proteins

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RNAi disguise identifies Brd4 as a therapeutic mark in acute myeloid leukaemia

Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R.; Herrmann, Harald; Sison, Edward A.; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J.; Johns, Christopher; Chicas, Agustin; Mulloy, James C.; Kogan, Scott C.; Brown, Patrick; Valent, Peter; Bradner, James E.; Lowe, Scott W.; Vakoc, Christopher R.

Nature (London, United Kingdom) (2011), 478 (7370), 524-528 CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized ~ dint of. altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to give force to oncogenic gene expression programs. Although chromatin alterations are, in fountain, reversible and often amenable to mix with ~s intervention, the promise of targeting like pathways therapeutically has been limited ~ dint of. an incomplete understanding of cancer-limited dependencies on epigenetic regulators. Here the authors depict a non-biased approach to scrutinize epigenetic vulnerabilities in acute myeloid leukemia (AML), ~y aggressive hematopoietic malignancy that is ~times assocd. with aberrant chromatin states. By screening a practice library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML peer model, the authors identify the protein bromodomain-contg. 4 (Brd4) being of the kind which being critically required for disease defence. Suppression of Brd4 using shRNAs or the dull-mol. inhibitor JQ1 led to iron antileukemic effects in vitro and in vivo, accompanied ~ the agency of terminal myeloid differentiation and elimination of leukemia resist cells. Similar sensitivities were obsd. in a difference of human AML cell lines and aboriginal patient samples, revealing that JQ1 has capacious activity in diverse AML subtypes. The personal estate of Brd4 suppression are, at least in part, due to its role in sustaining Myc modulation to promote aberrant self-renewal, that implicates JQ1 as a pharmacol. means to suppress MYC in cancer. The authors’ results settle small-mol. inhibition of Brd4 since a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the usefulness of RNA interference (RNAi) screening on the side of revealing epigenetic vulnerabilities that can be exploited for direct pharmacol. intervention.

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