title: Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation.
abstract: STAT (Signal Transducer and Activator of Transcription) transcription factors are constitutively activated in most hematopoietic cancers. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. miR-28 exerts negative effects on thrombopoietin receptor signaling and platelet formation. Here, we demonstrate that, in transformed hematopoietic cells, STAT5 and p53 must be synergistically bound to chromatin for induction of LPP/miR-28 transcription. Genome-wide association studies show that both STAT5 and p53 are co-localized on the chromatin at 463 genomic positions in proximal promoters. Chromatin binding of p53 is dependent on persistent STAT5 activation at these proximal promoters. The transcriptional activity of selected promoters bound by STAT5 and p53 was significantly changed upon STAT5 or p53 inhibition. Abnormal expression of several STAT5-p53 target genes (LEP, ATP5J, GTF2A2, VEGFC, NPY1R and NPY5R) is frequently detected in platelets of myeloproliferative neoplasm (MPN) patients, but not in platelets from healthy controls. In conclusion, persistently active STAT5 can recruit normal p53, like in the case of MPN cells, but also p53 mutants, such as p53 M133K in human erythroleukemia cells, leading to pathologic gene expression that differs from canonical STAT5 or p53 transcriptional programs.
authors.affiliation: 1] Ludwig Institute for Cancer Research, Brussels, Belgium [2] de Duve Institute, Université catholique de Louvain, Brussels, Belgium [3] Institute of Molecular Genetics, CNRS UMR5535, Université de Montpellier, Montpellier, France.
authors.forename: M
authors.initials: M
authors.lastname: Girardot
authors.affiliation: 1] Ludwig Institute for Cancer Research, Brussels, Belgium [2] de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Pecquet
authors.affiliation: 1] Ludwig Institute for Cancer Research, Brussels, Belgium [2] de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Chachoua
authors.affiliation: 1] Ludwig Institute for Cancer Research, Brussels, Belgium [2] de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Van Hees
authors.affiliation: Biotechnology and Cell Signalling, UMR 7242, Université de Strasbourg, CNRS, ESBS, Illkirch Cedex, France.
authors.forename: S
authors.initials: S
authors.lastname: Guibert
authors.affiliation: Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Ferrant
authors.affiliation: 1] Ludwig Institute for Cancer Research, Brussels, Belgium [2] de Duve Institute, Université catholique de Louvain, Brussels, Belgium [3] Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Knoops
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Baxter
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Beer
authors.affiliation: 1] Institut Gustave Roussy, INSERM U1009, Villejuif, France [2] AP-HP, Université Paris XII, Laboratoire d'Hématologie, PRB Cellulothèque hématologie, Hôpital Henri Mondor, Créteil, France.
authors.forename: S
authors.initials: S
authors.lastname: Giraudier
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Institut Gustave Roussy, INSERM U1009, Villejuif, France.
authors.forename: W
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Green
authors.affiliation: 1] Ludwig Institute for Cancer Research, Brussels, Belgium [2] de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: S N
authors.initials: SN
authors.lastname: Constantinescu
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050799:STAT5 Transcription Factor; D016159:Tumor Suppressor Protein p53