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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References
Constantinescu SN, Girardot M, Pecquet C . Mining for JAK-STAT mutations in cancer. Trends Biochem Sci 2008; 33: 122–131.
Yu H, Jove R . The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 2004; 4: 97–105.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.
James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. New Engl J Med 2005; 352: 1779–1790.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397.
Walz C, Ahmed W, Lazarides K, Betancur M, Patel N, Hennighausen L et al. Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood 2012; 119: 3550–3560.
Yan D, Hutchison RE, Mohi G . Critical requirement for Stat5 in a mouse model of polycythemia vera. Blood 2012; 119: 3539–3549.
Moucadel V, Constantinescu SN . Differential STAT5 signaling by ligand-dependent and constitutively active cytokine receptors. J Biol Chem 2005; 280: 13364–13373.
Nelson EA, Walker SR, Alvarez JV, Frank DA . Isolation of unique STAT5 targets by chromatin immunoprecipitation-based gene identification. J Biol Chem 2004; 279: 54724–54730.
Casetti L, Martin-Lanneree S, Najjar I, Plo I, Auge S, Roy L et al. Differential contributions of STAT5A and STAT5B to stress protection and tyrosine kinase inhibitor resistance of chronic myeloid leukemia stem/progenitor cells. Cancer Res 2013; 73: 2052–2058.
Girardot M, Pecquet C, Boukour S, Knoops L, Ferrant A, Vainchenker W et al. miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets. Blood 2010; 116: 437–445.
Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Nati Acad Sci USA 2003; 100: 8424–8429.
Rajala HL, Eldfors S, Kuusanmaki H, van Adrichem AJ, Olson T, Lagstrom S et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 2013; 121: 4541–4550.
Moriggl R, Gouilleux-Gruart V, Jahne R, Berchtold S, Gartmann C, Liu X et al. Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Mol Cell Biol 1996; 16: 5691–5700.
Nakatake M, Monte-Mor B, Debili N, Casadevall N, Ribrag V, Solary E et al. JAK2(V617F) negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms. Oncogene 2011; 31: 1323–1333.
Pecquet C, Diaconu CC, Staerk J, Girardot M, Marty C, Royer Y et al. Thrombopoietin receptor down-modulation by JAK2 V617F: restoration of receptor levels by inhibitors of pathologic JAK2 signaling and of proteasomes. Blood 2012; 119: 4625–4635.
Stark GR, Darnell JE Jr . The JAK-STAT pathway at twenty. Immunity 2012; 36: 503–514.
Fritsche M, Mundt M, Merkle C, Jahne R, Groner B . p53 suppresses cytokine induced, Stat5 mediated activation of transcription. Mol Cell Endocrinol 1998; 143: 143–154.
Liu F, Zhao X, Perna F, Wang L, Koppikar P, Abdel-Wahab O et al. JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell 2011; 19: 283–294.
Dawson MA, Bannister AJ, Gottgens B, Foster SD, Bartke T, Green AR et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 2009; 461: 819–822.
Mouzaki A, Panagoulias I, Dervilli Z, Zolota V, Spadidea P, Rodi M et al. Expression patterns of leptin receptor (OB-R) isoforms and direct in vitro effects of recombinant leptin on OB-R, leptin expression and cytokine secretion by human hematopoietic malignant cells. Cytokine 2009; 48: 203–211.
DeJong J, Bernstein R, Roeder RG . Human general transcription factor TFIIA: characterization of a cDNA encoding the small subunit and requirement for basal and activated transcription. Proc Natl Acad Sci USA 1995; 92: 3313–3317.
Higuti T, Tsurumi C, Kawamura Y, Tsujita H, Osaka F, Yoshihara Y et al. Molecular cloning of cDNA for the import precursor of human coupling factor 6 of H(+)-ATP synthase in mitochondria. Biochem Biophys Res Commun 1991; 178: 793–799.
Lin Y, Brown L, Hedley DW, Barber DL, Benchimol S . The death-promoting activity of p53 can be inhibited by distinct signaling pathways. Blood 2002; 100: 3990–4000.
Townsend PA, Scarabelli TM, Davidson SM, Knight RA, Latchman DS, Stephanou A . STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis. J Biol Chem 2004; 279: 5811–5820.
Chipoy C, Brounais B, Trichet V, Battaglia S, Berreur M, Oliver L et al. Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53. Oncogene 2007; 26: 6653–6664.
Kramer OH, Moriggl R . Acetylation and sumoylation control STAT5 activation antagonistically. JAKSTAT 2012; 1: 203–207.
Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. New Engl J Med 2013; 369: 2379–2390.
Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New Engl J Med 2013; 369: 2391–2405.
Shi S, Calhoun HC, Xia F, Li J, Le L, Li WX . JAK signaling globally counteracts heterochromatic gene silencing. Nat Genet 2006; 38: 1071–1076.
Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B . Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 1990; 249: 912–915.
Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol 2007; 17: 1298–1307.
Wood TJ, Sliva D, Lobie PE, Goullieux F, Mui AL, Groner B et al. Specificity of transcription enhancement via the STAT responsive element in the serine protease inhibitor 2.1 promoter. Mol Cell Endocrinol 1997; 130: 69–81.
Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000; 406: 207–210.
Borgel J, Guibert S, Li Y, Chiba H, Schubeler D, Sasaki H et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet 2010; 42: 1093–1100.
Huang da W, Sherman BT, Lempicki RA . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4: 44–57.
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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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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DOI: https://doi.org/10.1038/onc.2014.60
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