Oncogene interference through targeting of chromatin regulators
Abstract
The chromatin regulatory machinery is often exploited during tumorigenesis.1 For example, many of the central transcription factors in cancer biology (such as p53 and Myc) utilize chromatin regulators (CRs) as coactivators or corepressors to regulate their downstream target genes. Moreover, somatic mutation of CR-encoding genes is a common driver mechanism seen in many cancer types.2 Hence, CRs often govern gene expression programs that endow cancer cells with their hallmark capabilities. Since CRs also possess desirable biochemical properties for the design of small-molecule inhibitors, therapeutic targeting of CRs provides a rational approach for interfering with the aberrant signaling events that drive cancer progression.
A major challenge in developing CRs as drug targets lies in determining whether cancer cells harbor unique vulnerabilities among this class of regulators. The majority of CR gene mutations identified in cancer are loss-of-function, hence they do not provide straightforward opportunities for targeting. In addition, most CRs are ubiquitously expressed proteins with broad chromatin occupancy, properties that confuse evaluating their suitability as targets. To explore these issues, we have taken a genetic screening approach toward identifying CR vulnerabilities in the blood cancer acute myeloid leukemia (AML); specifically in the subset of disease caused by rearrangements of the mixed-lineage leukemia (MLL) gene. MLL is mutated via chromosomal translocation…
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