Cancer cells rely on oncogene-induced, hyper-proliferative signaling for growth and survival. c-Myc, a transcription factor which regulates cell cycle progression, cell growth and proliferation, is one of the most commonly overexpressed oncogenes in human cancer. Myc is overexpressed in 70% of human malignancies, including non-Hodgkin lymphoma, a cause of approximately 20,000 deaths in the United States each year. Despite decades of research into the functions and activity of Myc, much remains unresolved and there have been no successful therapies that target Myc to date. Recently, it has been proposed that targeting Myc indirectly may help overcome the lack of successful therapies for treating Myc-driven cancers. However, Myc regulation is highly complex and the identity and function of many of the proteins that regulate Myc activity remain unknown or poorly characterized. Thus, it is of critical importance to identify and evaluate proteins that interact wth Myc and regulate its function. We have preliminary data suggesting MTBP, a protein which we have previously shown to be linked to Myc-driven proliferation and lymphomagenesis, associates in a complex with Myc and regulates its oncogenic functions. Therefore, we hypothesize MTBP is a novel transcriptional regulator of Myc and has a critical role in lymphoma development and survival. To test this hypothesis, we propose two specific aims that utilize both in-vivo and in-vitro model systems. In the Aim 1, we will utilize molecular and biochemical strategies to elucidate the mechanism by which MTBP regulates Myc transcriptional activity.
In Aim 2, we will employ in-vivo mouse model systems to evaluate the oncogenic activity of MTBP and characterize its role in lymphoma development and survival. We will also utilize human lymphoma cell lines to correlate our findings with mice to humans and to provide clinical relevance. Our results will significantly enhance our understanding of how Myc is regulated and will characterize the functions of a novel protein that regulates Myc. We anticipate that our findings will identify a novel target for treating Myc- driven malignancies. The challenging, comprehensive training that students in the MD/PhD program at the Vanderbilt University School of Medicine undergo will allow me to fulfill the goals of this proposal and will provide me with the education necessary to be a successful, independent physician-scientist. Throughout my training, I will learn to think critically, evaluate data, develop novel hypotheses and successfully answer scientific questions in the laboratory. This will be accomplished through seminars, journal clubs, didactic coursework, scientific meetings, analysis of the literature and thoughtful discussions with my mentor, thesis committee and other scientists. The educational and career development objectives outlined in this proposal will help me fulfill my goal of becoming a successful, independent physician-scientist in cancer research.
Each year in the United States, approximately 70,000 people will be diagnosed with non-Hodgkin lymphoma, a common blood cancer, and approximately 20,000 individuals will die of this disease. Our studies on an oncogene that drives lymphoma will improve understanding of how lymphoma develops and the molecular processes necessary for its survival. The results of our study are expected to identify new targets for therapeutic intervention for patients suffering from lymphoma and likely other cancers.
| Puccetti, M V; Fischer, M A; Arrate, M P et al. (2017) Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution. Oncogene 36:2553-2564 |
