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
  • X-linked Nuclear Protein/deficiency*
  • X-linked Nuclear Protein/genetics*
  • Tumor Suppressor Protein p53/deficiency*
  • Tumor Suppressor Protein p53/genetics*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Telomere Homeostasis/genetics
  • Carcinogenesis/genetics
  • Carcinogenesis/metabolism
  • Zebrafish Proteins/deficiency*
  • Zebrafish Proteins/genetics*
  • Female
  • Male
  • Globins/genetics
  • Erythropoiesis
  • Animals, Genetically Modified
  • Neurofibromin 1/deficiency
  • Neurofibromin 1/genetics
  • Animals
  • Humans
  • Loss of Function Mutation
  • Disease Models, Animal
  • CRISPR-Cas Systems
  • Gene Knockout Techniques
  • Sarcoma, Experimental/etiology*
  • Sarcoma, Experimental/genetics
  • Sarcoma, Experimental/metabolism
(all 28)
PubMed
30970016 Full text @ PLoS Genet.
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
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
atrxzdf36/zdf36 (AB)standard conditionsDay 5
atrxzdf36/zdf36 (AB)standard conditionsDays 7-13
atrxzdf36/zdf36 (AB)standard conditionsDays 7-13 to Days 14-20
atrxzdf36/zdf36 (AB)standard conditionsDays 7-13 to Days 14-20
atrxzdf36/zdf36; la781Tgstandard conditionsDays 7-13
atrxzdf36/zdf36; la781Tgstandard conditionsDays 7-13
atrxzdf36/zdf36; la781Tgstandard conditionsDays 7-13
atrxzdf36/zdf36; la781Tgstandard conditionsDays 7-13
atrxzdf36/zdf36; la781Tgstandard conditionsDays 7-13
atrxzdf36/zdf36; la781Tgstandard conditionsDays 7-13
1 - 10 of 23
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ba2TgTransgenic Insertion
    la781TgTransgenic Insertion
      p301
        		Indel
        p303
          		Indel
          zdf1
            		Point Mutation
            zdf36
              		Indel
              zdf37
                		Indel
                zdf38
                  		Indel
                  1 - 8 of 8
                  Show
                  Human Disease / Model
                  Human Disease Fish Conditions Evidence
                  alpha thalassemia-X-linked intellectual disability syndromeTAS
                  alpha thalassemia-X-linked intellectual disability syndromeatrxzdf36/zdf36 (AB)standard conditionsIC
                  alpha thalassemia-X-linked intellectual disability syndrometp53zdf1/zdf1; atrxzdf37/+; nf1ap301/+; nf1bp303/p303standard conditionsIC
                  1 - 3 of 3
                  Show
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  atrxCRISPR1-atrxCRISPR
                  1 - 1 of 1
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                  Fish
                  Fish
                  AB
                  atrxzdf36/+ (AB)
                  atrxzdf36/zdf36 (AB)
                  atrxzdf36/zdf36; la781Tg
                  tp53zdf1/zdf1; atrxzdf37/+; nf1ap301/+; nf1bp303/p303
                  tp53zdf1/zdf1; atrxzdf37/+; nf1bp303/p303
                  tp53zdf1/zdf1; nf1ap301/+; nf1bp303/p303
                  tp53zdf1/zdf1; nf1bp303/p303
                  1 - 8 of 8
                  Show
                  Antibodies
                  No data available
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  GFPEFGGFP
                  1 - 2 of 2
                  Show
                  Mapping
                  No data available
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                  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.