Abstract 2892: A MYC-driven medulloblastoma model derived from human induced pluripotent stem cells

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Abstract Brain tumors are the most common cause of childhood oncological death, and medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current MB treatments yield five-year survival rates of 60-70%, but usually result in significant neurological, intellectual and physical disabilities. Recent gene expression studies have identified four MB subgroups, many of which have unique clinical and histopathological features. Patients with Group 3 MB are more likely to have aggressive and invasive tumors with large cell/anaplastic histology, and have the worst prognosis. Group 3 MB is characterized by amplification and overexpression oncogenic transcription factor MYC, herein referred to as MYC-driven MB. Modeling MYC-driven MB is critical for developing and testing potential therapies for this highly aggressive MB. Recently, murine MYC-driven MB models have been developed using mouse neural stem cells (NSCs) or neuronal precursor cells (NPCs). But human MB models derived from individual-specific cells are still lacking. Human induced pluripotent stem cells (iPSCs) can be differentiated into various types of cells and hold great promise for developing individual-specific disease models. It is valuable to develop MB models using human iPSCs from both MB patients and unaffected persons. In comparison with mouse-cell-derived MB models, human-iPSC-derived MB models will provide a unique and high-impact platform not only for personalized drug discovery but also for studying the role of individual's distinctive genetic background in carcinogen sensitivity and MB susceptibility. Transcription factor Atoh1 governs the development of cerebellar granule neurons and is essential for MB formation. Here, we induced Atoh1 in human iPSCs to differentiate these cells into NPCs. We further infected these Atoh1-induced NPCs with lentiviruses encoding a stabilized form of MYC (MYCT58A) and dominant-negative p53 (DNp53). These NPCs generated aggressive tumors after being transplanted into mouse cerebellum. NPCs infected by DNp53 alone did not form tumors after 90 days. These MYC-driven tumors were comprised of poorly differentiated, medium to large size cells which showed nuclear molding, prominent nucleoli and numerous mitotic (Ki67+) and apoptotic (Cleaved-Caspase-3+) cells. These tumors also expressed early neuronal lineage marker (β-tubulin III). All these features closely mimic human Group 3 MB. Moreover, we also established neurosphere cultures from these MYC-driven tumors to enrich cancer stem-like cells that have the capability for long-term self-renewal and tumor initiation upon serial transplantations. In summary, we established a novel human-iPSC-drived cancer model for modeling MYC-driven MB. Our results support the feasibility to recapitulate human cancers using progenies derived from human iPSCs. The iPSC-derived MB model we established will facilitate mechanistic studies and drug testing for human aggressive MB. Citation Format: Jonathan Sagal, Charles G. Eberhart, Mingyao Ying. A MYC-driven medulloblastoma model derived from human induced pluripotent stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2892. doi:10.1158/1538-7445.AM2015-2892