The long-term goal of this project is to understand at cellular and molecular levels the pathogenesis of neuroblastoma, a common childhood malignant tumor of neural crest origin that arises in the sympathetic nervous system. For this grant period, we will focus on Bmi-1, which is essential for the maintenance of stem cells through transcriptional repression of genes that control stem cell self-renewal proliferation, differentiation, apoptosis, and senescence. Based on the data from our preliminary studies, we hypothesize that Bmi-1 contributes to neuroblastoma development by maintaining sympathetic neural crest stem cells, from which neuroblastoma probably derives, and neuroblastoma stem cells, which drive tumor growth. We will test the hypothesis in both animal- and cell-based systems. In studies under AIM 1, we will define the role of Bmi-1 in neuroblastoma development. We will examine the effects Bmi-1 deficiency on neuroblastoma initiation and progression in MYCN mice, an animal model of the human disease. We will further assess its role in development of the stromal microenvironment suitable for neuroblastoma genesis. In studies under AIM 2, we will define the cellular basis for the oncogenic activity of Bmi-1 in neuroblastoma initiation and progression. We will examine the effects of Bmi-1 deficiency on malignant transformation and maintenance of sympathetic neural crest stem cells and neuroblastoma stem cells. We will determine how Bmi-1 deficiency may affect stem cell fate decisions: proliferation, differentiation, apoptosis, or senescence. In studies under AIM 3, we will elucidate the molecular mechanisms for the oncogenic activity of Bmi-1 in the pathogenesis of neuroblastoma. We will examine the role of Ink4a and ARF as tumor suppressors in neuroblastoma development in MYCN mice and as Bmi-1 targets in regulation of neuroblastoma cell proliferation and senescence. We will examine the role of Bim as a Bmi-1 target in regulation of neuroblastoma cell apoptosis. Finally, we will examine the role of HoxC9 as a Bmi-1 target in regulation of neuroblastoma cell differentiation. These studies should further our understanding of the molecular basis underlying neuroblastoma genesis and may suggest new targets for development of more effective and specific therapeutic agents for this deadly childhood cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Oncogenesis Study Section (MONC)
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Watson, Joanna M
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Georgia Regents University
Schools of Medicine
United States
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Wang, Xiangwei; Yang, Liqun; Choi, Jeong-Hyeon et al. (2014) Genome-wide analysis of HOXC9-induced neuronal differentiation of neuroblastoma cells. Genom Data 2:50-52
Zha, Y; Xia, Y; Ding, J et al. (2014) MEIS2 is essential for neuroblastoma cell survival and proliferation by transcriptional control of M-phase progression. Cell Death Dis 5:e1417
Ding, Jane; Li, Tai; Wang, Xiangwei et al. (2013) The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metab 18:896-907
Wang, Xiangwei; Choi, Jeong-Hyeon; Ding, Jane et al. (2013) HOXC9 directly regulates distinct sets of genes to coordinate diverse cellular processes during neuronal differentiation. BMC Genomics 14:830
Mao, L; Ding, J; Perdue, A et al. (2012) Cyclin E1 is a common target of BMI1 and MYCN and a prognostic marker for neuroblastoma progression. Oncogene 31:3785-95
Chen, Xin-Ya; Gu, Xiu-Ting; Saiyin, Hexige et al. (2012) Brain-selective kinase 2 (BRSK2) phosphorylation on PCTAIRE1 negatively regulates glucose-stimulated insulin secretion in pancreatic ?-cells. J Biol Chem 287:30368-75
Zha, Yunhong; Ding, Emily; Yang, Liqun et al. (2012) Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation. PLoS One 7:e40728
Mao, Ling; Ding, Jane; Zha, Yunhong et al. (2011) HOXC9 links cell-cycle exit and neuronal differentiation and is a prognostic marker in neuroblastoma. Cancer Res 71:4314-24
Wang, Huibo; Wu, Wenting; Wang, Hong-Wei et al. (2010) Analysis of specialized DNA polymerases expression in human gliomas: association with prognostic significance. Neuro Oncol 12:679-86
Alam, Goleeta; Cui, Hongjuan; Shi, Huilin et al. (2009) MYCN promotes the expansion of Phox2B-positive neuronal progenitors to drive neuroblastoma development. Am J Pathol 175:856-66

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