Abstract 476: Loss of chd5-mediated tumor suppression accelerates MYCN-driven neuroblastoma tumorigenesis in zebrafish

Abstract

Abstract Neuroblastoma is a childhood tumor of the peripheral sympathetic nervous system (PSNS) that originates from cells of the primitive neural crest. For the 40% of patients with high-risk disease, current therapies are often ineffective and long-term survival remains obstinately low. A major risk factor in neuroblastoma is hemizygous loss of the 1p36 chromosomal region, which has long been suspected to harbor one or more powerful tumor suppressor genes. Our studies indicate that loss of Chromodomain helicase DNA-binding protein 5 (chd5), which is in this deleted region, cooperates with MYCN overexpression to accelerate in vivo neuroblastoma tumorigenesis. Zebrafish chd5-null alleles were created utilizing both zinc-finger nuclease and TALEN technology. The resulting chd5 mutant fish exhibit abnormal development of the PSNS in the form of expansion of the superior cervical ganglia and enlargement of the interrenal gland (adrenal medulla). In order to examine the effect of chd5 haploinsuficiency on in vivo neuroblastoma tumorigenesis, chd5 mutant fish were crossed with the dbh:MYCN transgenic model resulting in neuroblastoma tumors. Consistent with a tumor suppressor function, chd5 haploinsufficient fish exhibit an accelerated neuroblastoma phenotype with tumors present beginning as early as 6 weeks compared to 15 weeks observed in wildtype fish. The chd5 protein can serve as one of two enzymatic components of the nucleosome remodeling and histone deacetylase (NuRD) complex, which is a repressor of gene expression and is reported to have diverse roles in regulating chromatin organization, developmental signaling and gene stability. Future studies will examine the mechanism and function of chd5 so that the pathways mediating tumor suppression can be elucidated and that essential proteins in these pathways can be targeted in ways that exploit the synthetic lethal relationships that are established. Citation Format: Mark W. Zimmerman, Shuning He, Jimann Shin, Shizhen Zhu, Marc Mansour, Keith Joung, Jinhua Quan, Timur Yusufzai, A. Thomas Look. Loss of chd5-mediated tumor suppression accelerates MYCN-driven neuroblastoma tumorigenesis in zebrafish. [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 476. doi:10.1158/1538-7445.AM2015-476