Supplementary MaterialsFigure 1figure supplemenrt 2source data 1: Resource data for Number 1figure product 2. Number 3source data 5: Genes utilized for analysis shown in Number 3D. elife-37202-fig3-data5.xlsx (75K) DOI:?10.7554/eLife.37202.018 Figure 3figure supplement 1source data 1: GSEA report and human tumor gene expression signatures utilized for GSEA comparing angiosarcoma, MPNST and ERMS to their human counterparts. elife-37202-fig3-figsupp1-data1.xlsx (25K) DOI:?10.7554/eLife.37202.011 Figure 3figure product 1source data 2: Differential gene expression for leukemias with respect to blood cells and kidney cells shown in Figure 3figure product 1D. Gene identifications correspond to SMARTseq and InDrop solitary cell sequencing from Tang et al. (2017), as indicated. elife-37202-fig3-figsupp1-data2.xlsx (38K) DOI:?10.7554/eLife.37202.012 Figure 3figure product 1source data 3: Genes utilized for analysis shown in Figure 3figure product 1E. elife-37202-fig3-figsupp1-data3.xlsx (44K) DOI:?10.7554/eLife.37202.013 Transparent reporting form. elife-37202-transrepform.docx (249K) DOI:?10.7554/eLife.37202.021 Data Availability StatementSequencing data has been deposited in GEO under accession code “type”:”entrez-geo”,”attrs”:”text”:”GSE109581″,”term_id”:”109581″GSE109581 The following dataset was generated: Myron S IgnatiusMadeline N HayesDavid M Langenau2018tp53 deficiency causes a wide tumor spectrum and raises embryonal rhabdomyosarcoma metastasis in zebrafishhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=”type”:”entrez-geo”,”attrs”:”text”:”GSE109581″,”term_id”:”109581″GSE109581Publicly available at the NCBI Gene Manifestation Omnibus (accession no. “type”:”entrez-geo”,”attrs”:”text”:”GSE109581″,”term_id”:”109581″GSE109581) The following previously published datasets were used: Qin TangDavid M Langenau2017Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at solitary cell resolution using RNA sequencing [Smart-seq]http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=”type”:”entrez-geo”,”attrs”:”text”:”GSE100911″,”term_id”:”100911″GSE100911Publicly available at the NCBI Gene Expression Omnibus (accession no. “type”:”entrez-geo”,”attrs”:”text”:”GSE100911″,”term_id”:”100911″GSE100911) Qin TangDavid M Langenau2017Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single cell resolution using RNA sequencing [inDrops]https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=”type”:”entrez-geo”,”attrs”:”text”:”GSE100910″,”term_id”:”100910″GSE100910Publicly available at the NCBI Gene Expression Omnibus (accession no. “type”:”entrez-geo”,”attrs”:”text”:”GSE100910″,”term_id”:”100910″GSE100910) Qin TangDavid M Langenau2017Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single cell resolution using RNA sequencing [bulk RNA-seq]https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=”type”:”entrez-geo”,”attrs”:”text”:”GSE100912″,”term_id”:”100912″GSE100912Publicly available at the NCBI Gene Expression Omnibus (accession no. “type”:”entrez-geo”,”attrs”:”text”:”GSE100912″,”term_id”:”100912″GSE100912) Abstract The tumor-suppressor gene is usually mutated in 50% of human tumors and Li-Fraumeni patients with germ collection inactivation are predisposed to developing cancer. Here, we generated deleted zebrafish that spontaneously develop malignant peripheral nerve-sheath tumors, angiosarcomas, germ cell TSA inhibition tumors, and an aggressive Natural Killer cell-like leukemia for which no animal model has been developed. Because the tp53 deletion was generated in syngeneic zebrafish, engraftment of fluorescent-labeled tumors could be dynamically visualized over time. Importantly, engrafted tumors shared gene expression signatures with predicted cells of origin in human tissue. Finally, we showed that enhanced invasion and metastasis in in Li-Fraumeni patients leads to malignancy predisposition early TSA inhibition in life and is associated with transformation in a broad range of target tissues (Malkin, 2011). is commonly inactivated by single amino acid mutations that create dominant-negative forms of the protein that inhibit efficient tetramer formation and block transcriptional activity (Muller and Vousden, 2014). In this setting, alleles likely alter transcriptional activity of TP53 and its related transcription factor family members, TP63 and TP73 (Lang et al., 2004; Olive et al., 2004). By contrast, deletion is expected to have less wide-ranging transcriptional effects that are confined to tetrameric transcription factor function. Regardless of the genetic alteration, TP53 transcriptional inactivation can lead to genomic instability and impaired apoptotic responses that often are predisposing to a wide array of cancers (Kastenhuber and Lowe, 2017; Muller and Vousden, 2014). To date, several murine genetic models have been developed to assess the effects of both loss- and gain-of-function mutations in malignancy (Donehower et TSA inhibition al., 1992; Harvey et al., 1993; Jacks et al., 1994; Lang et al., 2004; Lavigueur et al., 1989; Lee et al., 1994; Olive et al., 2004). Both inactivation has important implications in regulating the types of malignancy that develop, the time to onset, and the overall propensity for tumor progression (Lavigueur et al., 1989; Lee et al., 1994). For example, mice heterozygous for the 172His usually point mutation are predisposed to developing osteosarcoma while animals harboring the?270His mutation develop hemangiosarcoma and carcinoma TSA inhibition (Olive et al., 2004). By contrast, mice with homozygous deletion mainly develop lymphoma, with rare cases of angiosarcoma, undifferentiated sarcoma, osteosarcoma, rhabdomyosarcoma, testicular tumors, nervous system tumors, teratoma, and mammary carcinoma being reported (Donehower et al., 1992; Harvey et al., 1993; Jacks et al., 1994). Together, these data suggest that differences in gain- and loss-of-function alleles have profound effects on Rabbit Polyclonal to USP13 tumor onset and spectrum in genetically designed mice and yet, largely recapitulate the wide array of cancers observed in Li-Fraumeni patients. Importantly, a small subset of Li-Fraumeni syndrome patients harbor genomic deletions in the locus and cancers that develop in dominant-negative, heterozygous point-mutation service providers often display deletion of the second allele (Malkin, 2011). Thus, modeling total TP53 loss-of-function in different animal models will likely provide novel insights into human disease. is also generally mutated in human sarcomas and is predictive of poor end result (Taubert et al., 1996). For example, the locus.