Role of LMO1 in Neuroblastoma Initiation and Maintenance: Analysis in the Zebrafish model of Childhood Neuroblastoma

Background
Neuroblastoma is an embryonal tumor that is often hard to treat successfully, accounting for 10% of cancer-related deaths in childhood. We will use our recently developed zebrafish model of neuroblastoma to investigate intriguing recent discoveries made by our close collaborators, Dr. John Maris and his group, implicating the LMO1 gene in the development of neuroblastoma. A key question in neuroblastoma research is "why do some children develop neuroblastoma at a young age while others do not?" Dr. Maris and colleagues have found that inherited DNA sequence changes within LMO1 are strongly associated with susceptibility to neuroblastoma, implicating high levels of LMO1 expression as an important step in the onset of neuroblastoma. Our recent results show that overexpression of LMO1 in the zebrafish model markedly accelerates the onset and increases the penetrance of MYCN-induced neuroblastoma, providing evidence for the role of LMO1 overexpression in the initiation of neuroblastoma. 

Project Goal
In this 2014 Innovation Award application, we will use the very latest genome editing technology to program human DNA sequence changes into the zebrafish genome and then assess the regulation of lmo1 expression levels and the development of neuroblastoma.  We will also turn off LMO1 expression in established tumors to determine whether LMO1 is continuously required for tumor cell growth and survival in living zebrafish. Through these studies, we will determine how the LMO1 gene is regulated to promote neuroblastoma and define potentially "druggable" proteins upstream and downstream of LMO1 overexpression as candidate targets for the development of new therapies for this disease.