Activation of Myc oncogenic transcription factors is a hallmark of rapidly dividing malignancies. In lymphoma and leukemia Myc activation occurs either directly through chromosomal translocations or amplification, or indirectly as a required downstream target induced by other oncoproteins (e.g., BCR-ABL and others) activated in these tumors. The pervasive selection for Myc activation in cancer reflects its essential roles in regulating a vast cast of targets (well over 10% of the genome), including those that coordinate and control cell growth (mass) and division, cell metabolism, metastasis, and tumor angiogenesis. Fundamental studies supported by CA076379- 11A1, using the validated E?-Myc transgenic mouse model of human B cell lymphoma, have demonstrated that Myc-mediated activation of the Arf-p53 tumor suppressor pathway, and its selective regulation of the Bcl-2 circuit of apoptotic regulators, harness Myc-induced tumorigenesis. Accordingly, mutations in these checkpoints are common in Myc-driven malignancies in both mice and man. Our new Preliminary Studies have now revealed additional principles of Myc-induced lymphomagenesis. First, Myc disrupts early B cell development and we hypothesize that this differentiation block contributes to tumorigenesis. Second, Myc provokes the activation of distinct tumor suppressor pathways at different windows of B cell development.
In Specific Aim 1 we test the hypothesis that Myc controls the expression of select master regulators of B cell development to promote lymphomagenesis. Here we will define the mechanism by which Myc regulates the expression of these B cell developmental regulators, and we will determine their contribution to the lineage, progression and maintenance of Myc-induced lymphoma, and their roles in biasing the activation of tumor suppressor pathways. How oncogenes provoke activation of the Arf-p53 tumor suppressor pathway is a major thrust of oncology research. Our Preliminary Studies have shown that Arf induction by Myc is developmentally restricted, and they support the hypothesis that Myc induces Arf expression indirectly, specifically by regulating the expression of a key component of the Polycomb-Repressive Complex-1 (PRC1) that is required to stabilize repressive histone marks that normally epigenetically silence Arf transcription.
In Specific Aim 2 we will define the mechanism by which Myc regulates this PRC1 component, and we will determine its roles in controlling Arf transcription during lymphoma progression, in orchestrating the activation of the Arf-p53 pathway, and in regulating the development and maintenance of Myc-driven lymphoma. We believe that our proposed studies will identify new targets that can be exploited by therapeutics that broadly and effectively target malignancies having Myc involvement, especially leukemia and lymphoma.
The goals of the research proposed in the revised competitive renewal application of R01 CA0763793- 11A1 are to define new targets that are altered during Myc oncogene-driven lymphoma development, and to evaluate their roles in tumor progression and in maintenance of the malignant state. Using a validated mouse model of human B cell lymphoma and leukemia, our studies have shown that Myc alters the expression of master regulators of B cell differentiation that we propose contribute to lymphomagenesis, and they have also suggested a mechanism by which Myc triggers the activation of the Arf-p55 tumor suppressor pathway that prevents tumor development in both mice and man. Since Myc oncoproteins are activated in up to 70% of all cancers, our discoveries may provide the foundation for developing new agents that are broadly effectively in cancer prevention and treatment.
| Huang, Qingling; Chen, Lihong; Yang, Leixiang et al. (2018) MDMX acidic domain inhibits p53 DNA binding in vivo and regulates tumorigenesis. Proc Natl Acad Sci U S A 115:E3368-E3377 |
| Doherty, Joanne R; Yang, Chunying; Scott, Kristen E N et al. (2014) Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res 74:908-20 |
| Lu, Yuanzhi; Wu, Yongsheng; Feng, Xiaoling et al. (2014) CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis. J Clin Invest 124:1672-84 |
| Valentin-Vega, Yasmine A; Maclean, Kirsteen H; Tait-Mulder, Jacqueline et al. (2012) Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119:1490-500 |
| Joo, Joung Hyuck; Dorsey, Frank C; Joshi, Aashish et al. (2011) Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Mol Cell 43:572-85 |
| Ji, Hongkai; Wu, George; Zhan, Xiangcan et al. (2011) Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation. PLoS One 6:e26057 |
| den Hollander, Jurgen; Rimpi, Sara; Doherty, Joanne R et al. (2010) Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116:1498-505 |
| Old, Jennifer B; Kratzat, Susanne; Hoellein, Alexander et al. (2010) Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis. Mol Cancer Res 8:353-62 |
| Keller, Ulrich; Huber, Jurgen; Nilsson, Jonas A et al. (2010) Myc suppression of Nfkb2 accelerates lymphomagenesis. BMC Cancer 10:348 |
| Zhang, Ji; Randall, Mindy S; Loyd, Melanie R et al. (2009) Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation. Blood 114:157-64 |
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