Abstract LB-162: The onset of MYCN overexpression-induced neuroblastoma is accelerated by ALK mutation in zebrafish

Abstract

Abstract Neuroblastoma (NB) is the most common extracranial solid tumor in infancy and originates in the peripheral sympathetic nervous system (PSNS). High-risk NB is fatal in the majority of patients, despite intensive myeloablative chemotherapy. The MYCN oncogene is amplified in over 20% of NB, particularly in those with highest risk treatment failure. We have developed a zebrafish NB model by overexpressing human MYCN under the control of the dopamine-beta-hydroxylase (D) promoter specific for noradrenergic cells in the PSNS. Fish from this stable transgenic line developed tumors as early as 4 months of age with approximately 20% penetrance at 8 months of age. The tumors resemble human NB histologically, immunohistochemically, and ultrastructurally. The expression of MYCN suppressed the normal development of PSNS neurons and chromaffin cells in the head kidney during embryogenesis and in young adult fish. In some fish, tumor cells began to repopulate the interrenal gland of the head kidney by 2 months of age. Germline and somatic activating mutations have been identified in the ALK gene, which encodes a receptor tyrosine kinase, in human NB, including those with MYCN amplification. To assess cooperativity between amplified MYCN and mutant ALK genes in transformation, we generated a zebrafish stable transgenic line in which the activated mutant form of ALK (F1174L) was expressed under the control of the DßH promoter. These transgenic animals did not display an abnormal phenotype nor did they develop tumors during the first 6 months of life. In contrast, mutant ALK expression accelerated the onset of MYCN-induced neuroblastoma when the 2 genes were co-expressed in double transgenic fish, indicating that MYCN over-expression and activating ALK mutations can cooperate in tumorigenesis. Although co-expression of mutant ALK accelerated the onset of tumors, it did not rescue the MYCN-induced suppression of PSNS development, suggesting that an as-yet-unidentified tumor suppressor gene, possibly located on distal 1p in the human genome, may be lost to fulfill this role in NB tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-162.