A human stem cell model of neuroblastoma identifies four chromosome 17q genes that drive tumor initiation and progression.

Neuroblastoma is a pediatric solid malignancy that primarily arises from poorly differentiated sympathoadrenal cells in the developing autonomic nervous system. The neuroblastoma genetic landscape is characterized by a paucity of somatic mutations and a far more common occurrence of chromosome copy number variations (CNVs). Two of the most common genetic abnormalities in neuroblastoma are the amplification of MYCN and the unbalanced gain of the long arm of chromosome 17 (17q+), both of which correlate with poor prognosis. Although mouse models exist for MYCN-driven neuroblastoma, no mouse models exist for 17q+. Thus, the mechanism by which 17q + contributes to poor prognosis remains largely unknown. Here, we used a human pluripotent stem cell (PSC) model of neuroblastoma to show that 17q + cooperates with MYCN amplification to accelerate tumorigenesis compared to MYCN amplification alone. We identified six genes on 17q that are upregulated in both our 17q + PSC-derived tumors and 17q + neuroblastoma patient tumors compared to WT 17q, correlate with poor prognosis in neuroblastoma patients, and are overexpressed at the protein level in our MYCN/17q + tumors compared to MYCN alone. Of these six genes, knockdown of BIRC5, CDC6, IGF2BP1, or TK1 in MYCN/17q + cells increases tumor latency in vivo and contributes to tumor progression through diverse mechanisms. Furthermore, knockdown of CDC6, IGF2BP1, and TK1 in neuroblastoma patient-derived xenografts with 17q + slowed growth in vivo. Our findings provide new insights into potential candidate 17q drivers of neuroblastoma tumorigenesis and possible therapeutic vulnerabilities.