Overcoming the epigenetic and therapeutic barrier of EVI1-overexpressing cancers

Project Information

EVI1inCancer

Grant agreement ID: 677209

DOI

10.3030/677209

Project closed

EC signature date 29 February 2016

Start date 1 June 2016

End date 31 May 2021

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 094,00

EU contribution

€ 1 499 094,00

Coordinated by

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany

Periodic Reporting for period 4 - EVI1inCancer (Overcoming the epigenetic and therapeutic barrier of EVI1-overexpressing cancers)

Reporting period: 2020-12-01 to 2021-05-31

Summary of the context and overall objectives of the project

EVI1 is a proto-oncogene frequently activated in high-risk leukemias and other cancers (e.g. high-grade ovarian cancer, breast cancer), however the cause of EVI1 transcriptional activation and the mechanism of EVI1-induced transformation are poorly understood. At present, there are no therapeutic strategies to target EVI1-driven cancers. Understanding the mechanism underlying EVI1-activation will have implications for other oncogene-driven cancers and may reveal new targets for therapy. We aim to characterize the epigenetic landscape in EVI1+ leukemias and solid tumors and reveal the transcription factors governing aberrant EVI1 activation.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

EVI1 overexpression was assessed in a series of solid tumor cell line and non-3q AML models and functionally validated. Chromosome looping studies and active chromatin analysis revealed novel candidate enhancers and regulators of the EVI1 TAD and a potentially novel mechanism of EVI1 upregulation outside of AML. The transcription factor network of the hijacked master hematopoietic GATA2 enhancer was analyzed using targeted mass spectrometry, and candidate chromatin regulators are being validated. Noncanonical functions of HR proteins are addressed with respect to chromatin folding and organization. Within 3q-AML, endogenous regulatory elements have been assessed for their regulatory potential and pathogenic role in 3q-rearrangements. A murine GATA2 enhancer-hijacking model is being established that will resemble the human t(3;3) AML.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Potential novel therapeutic intervention strategies have been revealed in 3q AML and interdisciplinary collaboration with clinical partners led to initiation of a phase II clinical trial.
We expect to gain deeper insight into the underlying principle of oncogenic superenhancer formation, nominate novel therapeutic molecular candidate targets and contribute to the understanding of 3q-AML pathogenesis.

EVI1 ChIP-SICAP