Periodic Reporting for period 4 - EVI1inCancer (Overcoming the epigenetic and therapeutic barrier of EVI1-overexpressing cancers)
Okres sprawozdawczy: 2020-12-01 do 2021-05-31
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.
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.
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.
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.