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.
- MeSH
- aktivace transkripce MeSH
- akutní myeloidní leukemie genetika patologie MeSH
- játra patologie MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši knockoutované MeSH
- myši MeSH
- nádorový supresorový protein p53 genetika MeSH
- onkogenní proteiny v-myb genetika metabolismus MeSH
- promotorové oblasti (genetika) MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- protoonkogenní proteiny genetika MeSH
- regulace genové exprese u leukemie MeSH
- slezina patologie MeSH
- trans-aktivátory genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- buněčné linie mikrobiologie MeSH
- lidé MeSH
- Rickettsia patogenita MeSH
- Check Tag
- lidé MeSH
- MeSH
- aglutinační testy MeSH
- antigeny izolace a purifikace MeSH
- Coxiella imunologie MeSH
- erytrocyty imunologie MeSH
- fenoly MeSH
- hemaglutinační testy MeSH
- imunodifuze MeSH
- komplement fixační testy MeSH
- kožní testy MeSH
- králíci MeSH
- kyselina trichloroctová MeSH
- lidé MeSH
- morčata MeSH
- ovce MeSH
- pasivní kožní anafylaxe MeSH
- rozpouštědla MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- lidé MeSH
- morčata MeSH
- zvířata MeSH
