title: Aggressive acute myeloid leukemia in PU.1/p53 double-mutant mice.
abstract: 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.
authors.affiliation: 1] Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic [2] Department of Experimental Biomodels, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Basova
authors.affiliation: Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Pospisil
authors.affiliation: Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: F
authors.initials: F
authors.lastname: Savvulidi
authors.affiliation: Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Burda
authors.affiliation: Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Vargova
authors.affiliation: 1] Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic [2] Department of Pathology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: L
authors.initials: L
authors.lastname: Stanek
authors.affiliation: Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Dluhosova
authors.affiliation: Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: E
authors.initials: E
authors.lastname: Kuzmova
authors.affiliation: 1] Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic [2] Department of Medicine-Haematology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Jonasova
authors.affiliation: Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA.
authors.forename: U
authors.initials: U
authors.lastname: Steidl
authors.affiliation: Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, St James's University Hospital, University of Leeds, Leeds, UK.
authors.forename: P
authors.initials: P
authors.lastname: Laslo
authors.affiliation: 1] Department of Pathophysiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic [2] Department of Medicine-Haematology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: T
authors.initials: T
authors.lastname: Stopka
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020626:Oncogene Proteins v-myb / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D035683:MicroRNAs; D020626:Oncogene Proteins v-myb; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D000099232:Proto-Oncogene Protein Spi-1; C532623:Mirn155 microRNA, mouse; C489428:Myc protein, mouse