Regulation of Differentiation of Pediatric Embryonal Tumors- Neuroblastoma

Division Of Basic Sciences - Nci

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Abstract

Specific Aim 1. To identify key differentiation genes. Specific Aim 2- To determine the molecular mechanisms by which CASZ1 regulates differentiation. The first genome wide studies of CASZ1 in mammalian myoblast cells indicated that CASZ1 forms a feed-forward differentiation regulatory circuit with MYOD and MYOG to enhance expression of genes key to myogenic differentiation (Liu et al Nature Comm. 2020). CASZ1 is a 1p36 tumor suppressor gene, whose expression is silenced by 1pLOH and/or EZH2 mediated epigenetic suppression, however reconstitution studies show CASZ1 inhibits cell growth and induces morphologic differentiation. We used genome-wide assessments of CASZ1 DNA binding to delineate gene programs directly mediating growth arrest and differentiation. These studies are currently under review for publication. The study shows the loss of CASZ1 is linked to the oncogenic subversion of the NB Core Regulatory Circuit. Specific Aim 3. To delineate the enhancer landscape mediating NB differentiation. Studies from Project 2 aimed at identifying MYCN interactors, showed that MYCN interacted with transcription factors that form the NB Core Regulatory Circuit. A study showing coopertive binding of MYCN and the NB -CRC is currently under review at Cancer Research.