Currently, there is a 1 in 48 chance a person in the United States will develop non-Hodgkin's lymphoma in his/her lifetime, a malignancy with a 50% survival rate. Therefore, a greater understanding of the molecular mechanisms involved in lymphomagenesis should result in the development of new treatments to increase patient survival. This project will investigate the oncogene Myc and its regulation of apoptotic cell death through transcriptional control of microRNA, non-coding RNAs. Following Myc overexpression in untransformed cells, apoptosis is induced through multiple mechanisms to limit the tumorigenic consequences of inappropriate oncogene activation. Myc activates the p53 tumor suppressor pathway and simultaneously suppresses the expression of anti-apoptotic Bcl-2 proteins to induce apoptosis of untransformed cells. Evasion of apoptosis upon Myc overexpression is crucial for cellular transformation and tumor development. Recently, it was reported that Myc overexpression in tumor cells resulted in a global decrease in miRNA. It is of critical importance to understand the role Myc has on miRNA expression in untransformed conditions to determine whether Myc suppression of miRNA contributes to or is a consequence of tumorigenesis. Our preliminary data suggest that Myc overexpression in untransformed cells induces the expression of specific miRNA that target proteins involved in apoptosis. Therefore, we hypothesize that Myc overexpression in untransformed cells upregulates the expression of specific miRNA that subsequently target proteins to enhance apoptosis and limit the tumorigenic potential of oncogene activation. We also hypothesize that this function of Myc is dysregulated during tumorigenesis. To test these novel hypotheses, we propose two Specific Aims utilizing in vitro and in vivo approaches.
In Aim 1, we propose a combination of molecular and biological strategies to evaluate the effects of Myc-induced miRNA expression in untransformed cells and identify the miRNA targets in apoptotic pathways.
In Aim 2, we will use a mouse model and biological assays to assess the role of specific miRNA and their targets in apoptosis and lymphomagenesis, and how they can be exploited in cancer therapy. Results from our proposed experiments will significantly enhance understanding of Myc-regulated mechanisms that contribute to apoptosis that are inactivated in cancer, and provide insight for the development of treatments for lymphoma and the many other cancers that overexpress Myc. The didactic graduate training program at Vanderbilt University, an NCI designated Comprehensive Cancer Center, and the guidance from my mentor, Dr. Christine Eischen, will allow me to achieve the proposed goals and necessary scientific training to be successful. Through classes, seminars, literature discussions, symposia, meetings, and important one-on-one interactions with my mentor. I will gain critical scientific knowledge and career development guidance. The education, training, and career development program outlined in this proposal will support my goal of becoming an independent investigator in cancer biology. !
Currently, 1 out of every 48 people in the United States will develop a common blood cancer known as non-Hodgkin's lymphoma over their lifetime, and the survival rate from such a cancer is poor. Our studies will provide new insights into lymphoma development, and it is anticipated that results from our proposed experiments will reveal new targets for future cancer therapy.
|McGirt, Laura Y; Adams, Clare M; Baerenwald, Devin A et al. (2014) miR-223 regulates cell growth and targets proto-oncogenes in mycosis fungoides/cutaneous T-cell lymphoma. J Invest Dermatol 134:1101-7|
|Adams, Clare M; Eischen, Christine M (2014) Inactivation of p53 is insufficient to allow B cells and B-cell lymphomas to survive without Dicer. Cancer Res 74:3923-34|