Project description:With an overall 5%-10% incidence rate in acute myeloid leukemia (AML), the occurrence of TP53 mutations is low compared with that in solid tumors. However, when focusing on high-risk groups including secondary AML (sAML) and therapy-related AMLs, the frequency of mutations reaches up to 35%. Mutations may include loss of heterozygosity (LOH) or deletion of the 17p allele, but are mostly missense substitutions that are located in the DNA-binding domain. Despite elaborate research on the effects of TP53 mutations in solid tumors, in hematological malignancies, the effects of TP53 mutations versus loss of TP53 remain unclear and under debate. Here, we compared the cellular effects of a TP53 mutant and loss of TP53 in human hematopoietic stem and progenitor cells (HSPCs). We found that when expressing TP53 mutant or loss of TP53 using siRNA, CD34+/CD38- cells have a significantly enhanced replating potential, which could not be demonstrated for the CD34+/CD38+ population. Using RNA-sequencing analysis, we found a loss of expression of p53 target genes in cells with TP53 knockdown. In contrast, an increased expression of a large number of genes was observed when expressing TP53 mutant, resulting in an increase in expression of genes involved in megakaryocytic differentiation, plasma membrane binding, and extracellular structure organization. When binding of p53 wild type and p53 mutant was compared in cell lines, we found that mutant p53 binds to a large number of binding sites genomewide, contrary to wild-type p53, for which binding is restricted to genes with a p53 binding motif. These findings were verified in primary AMLs with and without mutated TP53. In conclusion, in our models, we identified overlapping effects of TP53 mutant and loss of TP53 on in vitro stem cell properties but distinct effects on DNA binding and gene expression.
2023-07-26 | GSE238181 | GEO
Project description:A Case report: Novel treatment for complicated pathological MIBC
Project description:Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified ARID1A, a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, our mouse genetic and single cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage dependent roles. Utilizing this unique vulnerability of Arid1a mutated GC cells, our combinatorial treatment with an epigenetic inhibitor and a p53 agonist selectively inhibited Arid1a heterozygous tumor growth, providing a novel therapeutic option for GC.
2021-03-16 | GSE144385 | GEO
Project description:Novel Lynch syndrome-causing mutation in the MLH1 gene accompanied by a p.R283C mutation in TP53: A case report
Project description:With an overall 5%-10% incidence rate in acute myeloid leukemia (AML), the occurrence of TP53 mutations is low compared with that in solid tumors. However, when focusing on high-risk groups including secondary AML (sAML) and therapy-related AMLs, the frequency of mutations reaches up to 35%. Mutations may include loss of heterozygosity (LOH) or deletion of the 17p allele, but are mostly missense substitutions that are located in the DNA-binding domain. Despite elaborate research on the effects of TP53 mutations in solid tumors, in hematological malignancies, the effects of TP53 mutations versus loss of TP53 remain unclear and under debate. Here, we compared the cellular effects of a TP53 mutant and loss of TP53 in human hematopoietic stem and progenitor cells (HSPCs). We found that when expressing TP53 mutant or loss of TP53 using siRNA, CD34+/CD38- cells have a significantly enhanced replating potential, which could not be demonstrated for the CD34+/CD38+ population. Using RNA-sequencing analysis, we found a loss of expression of p53 target genes in cells with TP53 knockdown. In contrast, an increased expression of a large number of genes was observed when expressing TP53 mutant, resulting in an increase in expression of genes involved in megakaryocytic differentiation, plasma membrane binding, and extracellular structure organization. When binding of p53 wild type and p53 mutant was compared in cell lines, we found that mutant p53 binds to a large number of binding sites genomewide, contrary to wild-type p53, for which binding is restricted to genes with a p53 binding motif. These findings were verified in primary AMLs with and without mutated TP53. In conclusion, in our models, we identified overlapping effects of TP53 mutant and loss of TP53 on in vitro stem cell properties but distinct effects on DNA binding and gene expression.
Project description:Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified ARID1A, a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, our mouse genetic and single cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage dependent roles. Utilizing this unique vulnerability of Arid1a mutated GC cells, our combinatorial treatment with an epigenetic inhibitor and a p53 agonist selectively inhibited Arid1a heterozygous tumor growth, providing a novel therapeutic option for GC.