Community Research and Development Information Service - CORDIS


ChromatinTargets Report Summary

Project ID: 336860
Funded under: FP7-IDEAS-ERC
Country: Austria

Mid-Term Report Summary - CHROMATINTARGETS (Systematic in-vivo analysis of chromatin-associated targets in leukemia)

In addition to DNA mutations, human cancers harbor complex changes in their epigenetic landscape that are required for maintaining malignant cell-fate programs. Chromatin regulators involved in this process have recently emerged as a promising targets for the development of cancer therapies. However, cancer-specific dependencies on these regulators cannot be predicted from genome data and often remain poorly understood at the mechanistic level. The overall goal of our project is to combine genetically engineered mouse models (GEMMs) and advanced functional-genetic approaches to systematically identify and mechanistically study chromatin-associated dependencies and candidate targets in various subtypes of leukemia. To this end, we have generated a panel of leukemia models (involving diverse driver mutations and tissue contexts) and constructed an optimized shRNAmir library targeting 615 known and predicted chromatin regulators. Through comparative screening of this library we have established systematic map of chromatin dependencies in diverse leukemia subtypes. In addition to factors that are particularly required in the presence of specific driver mutations, our studies reveal that some of the strongest chromatin dependencies are determined by the tissue/lineage context rather than the genetic makeup of leukemia cells. Following the systematic identification of leukemia-specific chromatin dependencies, our project seeks to explore mechanisms that underlie these phenomena and determine sensitivity and resistance to chromatin-targeted therapies. One major focus of these studies is on the BET-bromodomain containing histone reader BRD4, which we have previously discovered as a candidate therapeutic target in acute myeloid leukemia (AML). While numerous BET inhibitors have meanwhile entered clinical trials, the cellular determinants of sensitivity and resistance to these agents remain poorly understood. To explore these mechanisms, we have comprehensively profiled sensitive and resistant leukemias using dynamic RNA-seq, ChiP-seq and IP-MS analyses, and performed an RNAi screen to decipher resistance factors. Collectively, our studies reveal that leukemias can develop resistance to BET inhibition through rewiring the transcriptional regulation of key BRD4 target genes such as MYC. In both primary and acquired resistance, this process involves specific changes in the enhancer landscape and the activation and recruitment of WNT signaling, which functionally validates to drive resistance in leukemia models and may serve as a first biomarker for predicting resistance to BET inhibitors.

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