Overcoming the epigenetic and therapeutic barrier of EVI1-overexpressing cancers

Información del proyecto

EVI1inCancer

Identificador del acuerdo de subvención: 677209

DOI

10.3030/677209

Proyecto cerrado

Fecha de la firma de la CE 29 Febrero 2016

Fecha de inicio 1 Junio 2016

Fecha de finalización 31 Mayo 2021

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 499 094,00

Aportación de la UE

€ 1 499 094,00

Coordinado por

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany

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

Período documentado: 2020-12-01 hasta 2021-05-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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