Novel Oncogenic Drivers in Multiple Myeloma: Defining the Role of DIS3 Mutations

• Applicant: Julia Frede, Ph.D.
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 363385493

We have gained insight into the most significant driver events in multiple myeloma, a plasma cell derived cancer of the bone marrow, by comprehensive genomic analysis of over 200 myeloma patients. While we observed recurrent mutations in known oncogenes and tumor suppressor genes, we also identified DIS3 as a recurrently mutated gene. DIS3 mutations are found in 15 to 20 % of patients with multiple myeloma, and several lines of evidence suggest that DIS3 mutations play an important role as drivers of the disease, and possibly as therapeutic targets and mediators of drug resistance. Our aim is to assess how DIS3 mutations contribute to disease progression in multiple myeloma. We are proposing to study the functional effects of DIS3 mutations on cell proliferation, cell cycle and survival, and to define the molecular mechanisms how DIS3 mutations act as drivers of the disease. As a catalytic component of the RNA exosome, which is involved in the processing and degradation of various RNA species, DIS3 plays a central role in the regulation of RNA abundance. DIS3 loss of function has been shown to result in the accumulation of non-coding transcripts, thus permitting the identification of thousands of novel transcripts that under normal conditions are too unstable to detect. We propose to take this approach to identify specific RNA substrates that accumulate if DIS3 is functionally impaired and that play a role in the progression of multiple myeloma. Of particular interest are long non-coding and enhancer RNAs, which have been shown to act as substrates for DIS3 and which may play a role in the regulation of transcription. To this end, we will use DIS3 mutant myeloma cell lines, characterized by whole exome sequencing, and subject these to RNA-Sequencing. Further, we are aiming to use the CRISPR/Cas9 genome editing technology to create cell lines with specific DIS3 mutations, thus generating a tractable and relevant model system to study the functional and molecular effects of DIS3 mutations. We will validate our results in primary patient samples to ensure that our findings are relevant in a clinical setting. We envision that the profiling of the entire transcriptome in myeloma cells as a dependent variable of DIS3 will allow us to shed light on the role of non-coding RNAs in disease progression as well as in the regulation of gene expression more generally.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Jens Lohr, Ph.D.