PUBLICATION
suz12 inactivation in p53 and nf1 deficient zebrafish accelerates the onset of MPNSTs and expands the spectrum of tumor types to include adenocarcinoma, leukemia, and soft tissue sarcoma
- Authors
- Oppel, F., Ki, D.H., Zimmermann, M.W., Ross, K.N., Tao, T., Shi, H., He, S., Aster, J.C., Look, A.T.
- ID
- ZDB-PUB-200712-3
- Date
- 2020
- Source
- Disease models & mechanisms 13(8): (Journal)
- Registered Authors
- He, Shuning, Ki, Dong Hyuk, Look, A. Thomas, Oppel, Felix, Tao, Ting
- Keywords
- Leukemia, MPNST, NF1, P53, RAS-signaling, SUZ12
- Datasets
- GEO:GSE125040
- MeSH Terms
-
- MAP Kinase Kinase Kinases/antagonists & inhibitors
- MAP Kinase Kinase Kinases/metabolism
- Signal Transduction
- Neurofibromin 1/deficiency
- Neurofibromin 1/genetics*
- Animals, Genetically Modified
- Animals
- Soft Tissue Neoplasms/genetics
- Soft Tissue Neoplasms/metabolism
- Soft Tissue Neoplasms/pathology
- Neurofibrosarcoma/drug therapy
- Neurofibrosarcoma/genetics*
- Neurofibrosarcoma/metabolism
- Neurofibrosarcoma/pathology
- DNA Methylation
- Gene Silencing*
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics*
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Epigenesis, Genetic
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Disease Models, Animal
- Antineoplastic Agents/pharmacology
- Leukemia/genetics
- Leukemia/metabolism
- Leukemia/pathology
- Sarcoma/genetics
- Sarcoma/metabolism
- Sarcoma/pathology
- Tumor Suppressor Protein p53/deficiency
- Tumor Suppressor Protein p53/genetics*
- Gene Expression Regulation, Neoplastic
- Cell Transformation, Neoplastic/genetics*
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Protein Kinase Inhibitors/pharmacology
- Zebrafish/genetics*
- Zebrafish/metabolism
- PubMed
- 32651197 Full text @ Dis. Model. Mech.
Citation
Oppel, F., Ki, D.H., Zimmermann, M.W., Ross, K.N., Tao, T., Shi, H., He, S., Aster, J.C., Look, A.T. (2020) suz12 inactivation in p53 and nf1 deficient zebrafish accelerates the onset of MPNSTs and expands the spectrum of tumor types to include adenocarcinoma, leukemia, and soft tissue sarcoma. Disease models & mechanisms. 13(8):.
Abstract
Polycomb repressive complex 2 (PRC2) is an epigenetic regulator of gene expression that possesses histone methyltransferase activity. PRC2 tri-methylates lysine 27 of histone 3 proteins (H3K27me3) as a chromatin modification associated with repressed transcription of genes frequently involved in cell proliferation or self-renewal. Loss-of-function mutations in the PRC2 core subunit SUZ12 have been identified in a variety of tumors, including malignant peripheral nerve sheath tumors (MPNSTs). To determine the consequences of SUZ12 loss in the pathogenesis of MPNST and other cancers, we used CRISPR-Cas9 to disrupt the open reading frame of each of two orthologous suz12 genes in zebrafish: suz12a and suz12b We generated these knockout alleles in the germline of our previously described p53/nf1-deficient zebrafish model of MPNSTs. Loss of suz12 significantly accelerated the onset and increased the penetrance of MPNSTs compared to control zebrafish. Moreover, in suz12-deficient zebrafish, we detected additional types of tumors besides MPNSTs, including leukemia with histological characteristics of lymphoid malignancies, soft tissue sarcoma, and pancreatic adenocarcinoma, which were not detected in p53/nf1-deficient control fish, and are also contained in the human spectrum of SUZ12-deficient malignancies identified in the AACR Genie database. The suz12-knockout tumors displayed reduced or abolished H3K27me3 epigenetic marks and up-regulation of gene sets reported to be targeted by PRC2. Thus, these zebrafish lines with inactivation of suz12 in combination with loss of p53/nf1 provide a model of human MPNSTs and multiple other tumor types, which will be useful for mechanistic studies of molecular pathogenesis and targeted therapy with small molecule inhibitors.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping