Expanding the spectrum of CNS EWSR1-PATZ1 rearranged tumors: an infantile case with leptomeningeal dissemination
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ABSTRACT:
PROVIDER: PRJNA682176 | ENA |
REPOSITORIES: ENA
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Project description:This case shows similarities with 2 previously reported cases, including intraventricular location, histologic appearance (pushing borders, oligodendrocyte-like morphology, rich vascular network) and immunophenotype with co-expression of OLIG2, GFAP and synaptophysin. The onset in an infant, the presence of a high-grade component and the leptomeningeal dissemination, however, have not been previously reported in EWSR1-PATZ1 rearranged tumors, expanding the clinico-pathological spectrum.
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Project description:We report on a case of EWSR1-PATZ1 rearranged brain tumor occurring in a 17 month-old child, originally interpreted as an infantile glioblastoma. Our case shows important analogies with the 2 previously reported cases, including the intraventricular location, the histologic appearance (pushing borders, oligodendrocyte-like morphology, rich vascular network) and the glioneural immunophenotype, supporting the role of these features as relevant clues to the diagnosis. On the other hand, our case displays unique characteristics, i.e. the onset in an infant, the presence of a focal high-grade component and the leptomeningeal dissemination, pointing to the importance of considering this entity in the differential diagnosis of an infantile glial/glioneural tumor.
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Project description:Insults to cellular health cause p53 protein accumulation and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel inhibitory role of PATZ1 on the p53 protein marks it as a proto-oncogene. PATZ1 deficient cells have reduced proliferative capacity which we assess by RNASeq and real time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage inducing drug doxorubicin results in the loss of the PATZ1 transcription factor, as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53 dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway. RNA-seq was used to define differentially expressed genes in wild-type and PATZ1-/- MEFs. Each sample was represented in triplicate.
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Project description:Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma HepG2 cells. PATZ1 level was found to be ectopically expressed in hepatocellular carcinoma cells compared to normal primary human hepatocytes, thus affirming its relevance in liver cancer. Our gene expression microarray and PATZ1 ChIP-seq analysis further revealed strong enrichment in gene ontology terms related to cellular proliferation. Importantly, siRNA-mediated PATZ1 knockdown in HepG2 cells led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Furthermore, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its promoter activity. Additionally, we found that PATZ1 associates with p53 and the absence of p53 abrogated the PATZ1-mediated regulation of CDKN1B expression. In conclusion, our study provides novel mechanistic insights into the role of PATZ1 in liver cancer progression, thereby providing a promising therapeutic intervention to alleviate tumor burden in liver cancer.
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Project description:Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma HepG2 cells. PATZ1 level was found to be ectopically expressed in hepatocellular carcinoma cells compared to normal primary human hepatocytes, thus affirming its relevance in liver cancer. Our gene expression microarray and PATZ1 ChIP-seq analysis further revealed strong enrichment in gene ontology terms related to cellular proliferation. Importantly, siRNA-mediated PATZ1 knockdown in HepG2 cells led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Furthermore, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its promoter activity. Additionally, we found that PATZ1 associates with p53 and the absence of p53 abrogated the PATZ1-mediated regulation of CDKN1B expression. In conclusion, our study provides novel mechanistic insights into the role of PATZ1 in liver cancer progression, thereby providing a promising therapeutic intervention to alleviate tumor burden in liver cancer.
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Project description:Insults to cellular health cause p53 protein accumulation and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel inhibitory role of PATZ1 on the p53 protein marks it as a proto-oncogene. PATZ1 deficient cells have reduced proliferative capacity which we assess by RNASeq and real time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage inducing drug doxorubicin results in the loss of the PATZ1 transcription factor, as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53 dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway.
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