Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock


Presence of mutant p53 increases stem-cell frequency and is associated with reduced binding to classical TP53 binding sites in cell lines and primary AMLs.


With an overall 5-10% incident rate in AML, occurrence of TP53 mutations are low compared to 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 to the effects of TP53 mutations in solid tumors, in hematological malignancies, the effects of TP53 mutations vs. loss of TP53 is still 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 significant enhanced re-plating 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 knock-down. In contrast, an increased expression of a large number of genes was shown when expressing TP53 mutant, resulting in an increase in expression of genes involved in megakaryocytic differentiation, plasma membrane binding and extracellular structure organization. When comparing binding of p53 wild-type and p53 mutant in cell lines, we found that mutant p53 binds to a large number of binding sites genome-wide, in 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 between TP53 mutant and loss of TP53 on in-vitro stem cell properties but distinct effects on DNA binding and gene expression.

Authors: Gerritsen M, Hilgendorf S, Yi G, Wierenga ATJ, Schuringa JJ, Martens JHA, Vellenga E,
Journal: Exp Hematol;2022 110:39-46 doi:10.1016/j.exphem.2022.03.007
Year: 2022
PubMed: PMID: 35315319 (Go to PubMed)