Aggressive acute myeloid leukemia in PU.1/p53 double-mutant mice
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24121269
DOI
10.1038/onc.2013.414
PII: onc2013414
Knihovny.cz E-resources
- MeSH
- Transcriptional Activation MeSH
- Leukemia, Myeloid, Acute genetics pathology MeSH
- Liver pathology MeSH
- Humans MeSH
- MicroRNAs genetics metabolism MeSH
- Disease Models, Animal MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Tumor Suppressor Protein p53 genetics MeSH
- Oncogene Proteins v-myb genetics metabolism MeSH
- Promoter Regions, Genetic MeSH
- Proto-Oncogene Proteins c-myc genetics metabolism MeSH
- Proto-Oncogene Proteins genetics MeSH
- Gene Expression Regulation, Leukemic MeSH
- Spleen pathology MeSH
- Trans-Activators genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- MicroRNAs MeSH
- Mirn155 microRNA, mouse MeSH Browser
- Myc protein, mouse MeSH Browser
- Tumor Suppressor Protein p53 MeSH
- Oncogene Proteins v-myb MeSH
- proto-oncogene protein Spi-1 MeSH Browser
- Proto-Oncogene Proteins c-myc MeSH
- Proto-Oncogene Proteins MeSH
- Trans-Activators MeSH
PU.1 downregulation within hematopoietic stem and progenitor cells (HSPCs) is the primary mechanism for the development of acute myeloid leukemia (AML) in mice with homozygous deletion of the upstream regulatory element (URE) of PU.1 gene. p53 is a well-known tumor suppressor that is often mutated in human hematologic malignancies including AML and adds to their aggressiveness; however, its genetic deletion does not cause AML in mouse. Deletion of p53 in the PU.1(ure/ure) mice (PU.1(ure/ure)p53(-/-)) results in more aggressive AML with shortened overall survival. PU.1(ure/ure)p53(-/-) progenitors express significantly lower PU.1 levels. In addition to URE deletion we searched for other mechanisms that in the absence of p53 contribute to decreased PU.1 levels in PU.1(ure/ure)p53(-/-) mice. We found involvement of Myb and miR-155 in downregulation of PU.1 in aggressive murine AML. Upon inhibition of either Myb or miR-155 in vitro the AML progenitors restore PU.1 levels and lose leukemic cell growth similarly to PU.1 rescue. The MYB/miR-155/PU.1 axis is a target of p53 and is activated early after p53 loss as indicated by transient p53 knockdown. Furthermore, deregulation of both MYB and miR-155 coupled with PU.1 downregulation was observed in human AML, suggesting that MYB/miR-155/PU.1 mechanism may be involved in the pathogenesis of AML and its aggressiveness characterized by p53 mutation.
References provided by Crossref.org
Combined Approach to Leukemic Differentiation Using Transcription Factor PU.1-Enhancing Agents
