ATRT-02. INTERACTIONS BETWEEN SMARCB1 AND CELLULAR DIFFERENTIATION STATE IN THE GENESIS OF ATYPICAL TERATOID RHABDOID TUMORS

Abstract

AbstractAtypical teratoid rhabdoid tumors (ATRT) are challenging pediatric brain tumors which are predominantly associated with inactivation of the gene SMARCB1 (aka INI1). As SMARCB1 is a conserved subunit of the chromatin remodeling BAF complex, we hypothesize that the effect of its loss of function is influenced by the epigenetic landscape of the cell in which deletion occurs, resulting in constrained age of onset and tissue specificity of tumor formation. To address this question, we generated a cell-based model of ATRT using an inducible SMARCB1 loss of function system in human induced pluripotent stem cells (iPSCs). With this model, we are investigating the molecular impact of SMARCB1 deletion on pluripotent and progenitor cells, with the aim of determining the importance of cell type and stage of differentiation in the growth of these tumors. Loss of SMARCB1 in pluripotent cells has been shown to initiate cell death, suggesting that a tissue-specific progenitor cell or further differentiated cell type is more likely to represent the cell of origin of ATRT. Ultimately, this model will be used to identify novel, therapeutically actionable targets which contribute to the phenotype of these tumors and to further understand the relationship between cell epigenetic identity and oncogenicity.