PUBLICATION
Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies
- Authors
- Oppel, F., Tao, T., Shi, H., Ross, K.N., Zimmerman, M.W., He, S., Tong, G., Aster, J.C., Look, A.T.
- ID
- ZDB-PUB-190411-8
- Date
- 2019
- Source
- PLoS Genetics 15: e1008039 (Journal)
- Registered Authors
- He, Shuning, Look, A. Thomas, Oppel, Felix, Shi, Hui, Tao, Ting, Zimmerman, Mark
- Keywords
- none
- Datasets
- GEO:GSE125040
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- CRISPR-Cas Systems
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Disease Models, Animal
- Erythropoiesis
- Female
- Gene Knockout Techniques
- Globins/genetics
- Humans
- Loss of Function Mutation
- Male
- Neurofibromin 1/deficiency
- Neurofibromin 1/genetics
- Sarcoma, Experimental/etiology*
- Sarcoma, Experimental/genetics
- Sarcoma, Experimental/metabolism
- Telomere Homeostasis/genetics
- Tumor Suppressor Protein p53/deficiency*
- Tumor Suppressor Protein p53/genetics*
- X-linked Nuclear Protein/deficiency*
- X-linked Nuclear Protein/genetics*
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/deficiency*
- Zebrafish Proteins/genetics*
- PubMed
- 30970016 Full text @ PLoS Genet.
Citation
Oppel, F., Tao, T., Shi, H., Ross, K.N., Zimmerman, M.W., He, S., Tong, G., Aster, J.C., Look, A.T. (2019) Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies. PLoS Genetics. 15:e1008039.
Abstract
The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping