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  • Original Article
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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.

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Acknowledgements

We thank Guido Bommer for invaluable p53 reagents and extremely useful criticisms and suggestions. We are grateful for generous support to SNC from the FRS-FNRS, Belgium (Mandat d’Impulsion and FRSM), the Salus Sanguinis Foundation, the Action de Recherche Concertée projects MEXP31C1 and ARC10/15–027 of the University catholique de Louvain, Brussels, the Fondation contre le Cancer, Brussels, the PAI Programs BCHM61B5 and Belgian Medical Genetics Initiative (BeMG), Belgium and the Atlantic Philanthropies, New York (for SNC). RM was supported by SFB-F2807/SFB-F4707 from the Austrian Science Fund (FWF).

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Correspondence to M Girardot or S N Constantinescu.

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Girardot, M., Pecquet, C., Chachoua, I. et al. Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation. Oncogene 34, 1323–1332 (2015). https://doi.org/10.1038/onc.2014.60

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