Aggressive acute myeloid leukemia in PU.1/p53 double-mutant mice

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 i...

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Published in:	Oncogene Vol. 33; no. 39; pp. 4735 - 4745
Main Authors:	Basova, P, Pospisil, V, Savvulidi, F, Burda, P, Vargova, K, Stanek, L, Dluhosova, M, Kuzmova, E, Jonasova, A, Steidl, U, Laslo, P, Stopka, T
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 25-09-2014 Nature Publishing Group
Subjects:	631/67/581 692/420/755 692/699/67/1990/283/1897 Acute myeloid leukemia Animals Apoptosis Cell Biology Disease Models, Animal Gene deletion Gene Expression Regulation, Leukemic Gene mutations Genetics Hematopoietic stem cells Human Genetics Humans Identification and classification Internal Medicine Leukemia Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - pathology Liver - pathology Medicine Medicine & Public Health Mice Mice, Knockout MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism miRNA Mutation Oncogene Proteins v-myb - genetics Oncogene Proteins v-myb - metabolism Oncology original-article p53 Protein Pathogenesis Progenitor cells Promoter Regions, Genetic Properties Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism PU.1 protein Spleen - pathology Stem cells Trans-Activators - genetics Transcriptional Activation Tumor suppressor genes Tumor Suppressor Protein p53 - genetics Tumors AML leukemia microRNA differentiation PU.1 p53
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2013.414