Abstract IA24: Transcriptional regulators as cancer dependencies

Abstract

Abstract Broad alterations in the rate of gene transcription are necessary, and often sufficient, for cells to undergo malignant transformation. As a consequence, cancer cells are vulnerable to perturbations of individual transcription regulators, including DNA-binding transcription factors and general cofactors. Our laboratory has taken a functional-genomics approach to identify essential transcriptional regulators in cancer cells in an effort to expose opportunities for therapeutic intervention. Our initial efforts used shRNA screening to identify the BET bromodomain protein BRD4 as a targetable non-oncogene dependency in acute myeloid leukemia. More recently, we have pursued the use CRISPR-Cas9 genome editing as a tool for annotating essential transcriptional regulators in cancer. In my presentation, I will review our current understanding of BRD4 as a therapeutic target in leukemia, focusing on the upstream and downstream factors that support BRD4-dependent transcriptional activation. I will also present our use of CRISPR-Cas9 to identify and validate therapeutic targets in cancer, which exploits the heterogeneity of Cas9-induced indel mutations to infer structure-function relationships of individual protein domains. Citation Format: Christopher Vakoc. Transcriptional regulators as cancer dependencies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA24.