Molecular characterization of FOXO1 and SRF oncogenic alterations
(2022)
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- Abstract
- Mistakes are daily introduced in our DNA code and processed by the cellular maintenance machinery. Despite a high-quality control, some errors escape the repair system and can cause mild to severe cellular dysfunctions depending on their type, location, and time of occurrence. Accumulation of genomic aberrations in a cell subset can promote the development of cancer. The study of the molecular mechanisms that drive tumorigenesis is essential to decipher the biology of cancer and to offer new options for diagnosis and targeted therapies. Through this work, we explored the world of transcription factors and their genomic alterations associated with cancer. Besides classical activating mutations of oncogenes and tumor suppressor genes inactivation, we exposed the complexity of biological consequences of single base substitutions, as well as major genetic events like the creation of new chimeric fusion proteins. The first study highlighted a new category of FOXO1 mutations in non-Hodgkin lymphoma. Whereas hotspot mutations in the N-terminus of FOXO1 are known to prevent nuclear export and provide a constitutive transcriptional activity, we focused on point mutations clustered in the DNA-binding domain of FOXO1. As predicted by their location, they affected DNA binding and led to a decrease in transcriptional activity. These findings underlined the complex role of FOXO1 and questioned its oncogenic status in B-cell lymphoma. The second study identified activation mechanisms of newly reported fusion genes involving the SRF transcription factor in soft tissue tumors with myoid features. Over the last years, SRF gene rearrangements were reported in the literature, including a few in our laboratory, but none of them were functionally studied. Here, we focused on four fusions, involving partner genes of different nature: SRF-RELA, SRF-FOXO1, SRF-ICA1L, and SRF-PDGFRβ. They all showed constitutive transcriptional activities and aberrant gene expression profiles, which could potentially lead to tumorigenesis. To our knowledge, this is the first attempt to understand the molecular function of those fusion genes. In conclusion, this work identified new oncogenic mechanisms driven by transcription factor alterations, which complements the published clinical data and provides new insights into the biology of non-Hodgkin lymphomas and myoid soft tissue tumors.
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Sablon, A. (2022). Molecular characterization of FOXO1 and SRF oncogenic alterations. https://hdl.handle.net/2078.5/101418