Define the role of chromosome 17q gain in neuroblastoma malignancy - PROJECT SUMMARY/ABSTRACT Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. The cell of origin for NB is believed to be sympathoadrenal cells that are derived from trunk neural crest cells. Recurring mutations are exceedingly rare in NB, while chromosome copy number changes are more robust. The most frequent chromosome copy number change is gain of chromosome 17q (17q+), which occurs in ~70- 80% of NB tumors and correlates with poor survival. Although the gold standard to evaluate if a genetic abnormality promotes tumorigenesis is to use genetically engineered mouse models, mouse and human chromosomes do not align. Thus, even though the prevalence of 17q+ in NB has been known for decades, no study has shown a functional effect for 17q+. We recently optimized a human stem cell model of NB in which human pluripotent stem cells (PSC) are differentiated toward sympathoadrenal cells and implanted orthotopically into immunocompromised mice. This model allows us to introduce genetic changes either at the PSC stage or at different stages during sympathoadrenal differentiation. In addition, we obtained human embryonic stem cells (ESC) that spontaneously acquired an extra copy of chromosome 17q. Our Preliminary Data demonstrated gain of chromosome 17q is insufficient to generate tumors in sympathoadrenal cells. However, the combination of MYCN with 17q+ accelerates tumorigenesis compared to MYCN alone. In addition, we found 17q+ tumors promote resistance to chemotherapy. Therefore, we hypothesize that chromosome 17q gain contributes to NB tumorigenesis and malignancy. Here, we propose three Aims using the model and cell lines described above to: 1) compare the tumorigenic potential of 17q+ and MYCN in immature cells that give rise to sympathoadrenal cells; 2) determine genes on chromosome 17q that cooperate with MYCN to accelerate tumorigenesis and promote chemotherapy resistance; and 3) identify vulnerabilities in MYCN/17q+ NB tumors. Successful completion of these studies will provide critical insight into the role of chromosome 17q gain in NB tumorigenesis and point to novel therapeutic strategies to potentially overcome chemotherapy resistance.
