Journal
GENES & DEVELOPMENT
Volume 34, Issue 19-20, Pages 1316-1329Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.339978.120
Keywords
SMARCB1; ATRT; iPSC; organoid; BAF complex; neural development; tumor modeling
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Funding
- Padres Pedal the Cause/RADY grant [PTC2017]
- National Institute of General Medical Sciences [T32GM008666]
- National Institute of Neurological Diseases and Stroke [R01-NS080939]
- Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship
- National Institutes of Health SIG grant [S10 OD026929]
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Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure that causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.
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