The Myc oncogene is overexpressed or dysregulated in at least 70% of all human malignancies, including B cell lymphomas. Myc is a transcription factor that drives cell cycle progression and induces cellular transformation that results in tumor development. Although significant advances have been made in recent years elucidating the genes that inhibit or contribute to Myc-induced tumor development, very little is known about the signaling pathways that are activated by Myc at any stage of tumor development. Moreover, the signaling pathways that are involved in cancers that become addicted or rely on Myc to continue to survive and grow remain unresolved. We have begun investigations into these open questions about Myc. We have recently determined that Myc activates the Ras signaling pathway in untransformed B cells, which inhibits Myc- induced apoptosis and significantly contributes to the transforming activity of Myc during B cell lymphomagenesis. However, it is unclear whether other signaling pathways are altered by Myc activity that contribute to the transformation ability of Myc, and if the Ras signaling pathway or other pathways are a factor in the oncogene addiction of the cancers that overexpress Myc. In addition, not all of the cells in a population may respond in the same way to Myc activation, resulting in population heterogeneity in response to Myc. Therefore, we hypothesize that in normal B cells, multiple signaling pathways are induced by Myc in the initial stages of transformation, and some of these contribute to lymphoma development and others to cell death. We also hypothesize that specific signaling pathways are required for Myc-addicted B cell lymphomas to grow and survive. To address these hypotheses we propose two Specific Aims.
Aim 1 will focus on the signaling pathways altered by Myc in untransformed B cells.
Aim 2 will focus on the pathways that mediate Myc addiction in B cell lymphomas. Recent advances in technology now allow analysis of signaling in single cells in a population, and dozens of individual signaling events on a per cel basis. Single cell analysis of signaling events will determine the pathways that are activated by Myc and the range of reactions to Myc in each Aim. Completion of these studies will significantly advance understanding into the initiating signaling events in Myc- induced B cell transformation and the pathways that contribute to Myc oncogene addiction. Our studies are also likely to result in the elucidation of novel therapeutically targetable pathways in B cell lymphoma.
The Myc oncogene is overexpressed or dysregulated in at least 70% of human cancers, including B cell lymphomas, and is critical for tumor cell growth and survival. Our studies will reveal the pathways that are activated by Myc prior to tumor development and required for the effects of this protein after lymphomas have formed. Results from this project should lead to the identification of new therapeutic targets for the treatment of lymphoma and the many other malignancies that rely on Myc.
| Moyo, T K; Wilson, C S; Moore, D J et al. (2017) Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to Btk inhibition. Oncogene 36:4653-4661 |
| Adams, Clare M; Mitra, Ramkrishna; Gong, Jerald Z et al. (2017) Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW. Clin Cancer Res 23:7119-7129 |
