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The JAK-STAT pathway and hematopoietic stem cells from the JAK2 V617F perspective

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Staerk, Judith [-] Constantinescu, Stefan N. [UCL]

Janus kinases (JAKs) are non-receptor tyrosine kinases essential for activation of signaling mediated by cytokine receptors that lack catalytic activity, including receptors for erythropoietin, thrombopoietin, most interleukins and interferon. Upon hormone binding, JAKs phosphorylate tyrosine residues in the receptor cytoplasmic domains and in JAKs themselves leading to recruitment and activation of downstream signaling proteins such as signal transducer and activator of transcription (STAT). The JAK-STAT pathway is important for functional hematopoiesis and several activating mutations in JAK proteins have recently been described as underlying cause of blood disorders. One of the best studied examples is the JAK2 V617F mutant which is found in 95% of polycythemia vera patients and 50% of patients suffering from essential thrombocythemia and primary myelofibrosis. Much effort has been made to understand how the JAK2 V617F affects hematopoietic stem cell (HSC) renewal and lineage differentiation, since convincing evidence has been provided to support the notion that the mutation is acquired at the HSC level. We discuss several in vivo models that support contrary conclusions with respect to the advantage given to HSCs by JAK2 V617F. Moreover, we provide the current knowledge about STAT5 activation and its link to HSC expansion as well as amplification of the erythroid compartment. Evidence for both JAK2 V617F mutated HSCs exhibiting skewed differentiation potential and for amplification occurring after erythroid commitment has been provided, and we will discuss whether this evidence is relevant for the „disease.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2012
Language Anglais
Journal information "JAK-STAT" - Vol. 1, no.3, p. 184-190 (2012)
Peer reviewed yes
Publisher Landes Bioscience
issn 2162-3988
e-issn 2162-3996
Publication status Publié
Affiliation UCL - SSS/DDUV - Institut de Duve
Links
  1. Dameshek W, Blood, 6, 372 (1951)
  2. James Chloé, Ugo Valérie, Le Couédic Jean-Pierre, Staerk Judith, Delhommeau François, Lacout Catherine, Garçon Loïc, Raslova Hana, Berger Roland, Bennaceur-Griscelli Annelise, Villeval Jean Luc, Constantinescu Stefan N., Casadevall Nicole, Vainchenker William, A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera, 10.1038/nature03546
  3. Kralovics Robert, Passamonti Francesco, Buser Andreas S., Teo Soon-Siong, Tiedt Ralph, Passweg Jakob R., Tichelli Andre, Cazzola Mario, Skoda Radek C., A Gain-of-Function Mutation ofJAK2in Myeloproliferative Disorders, 10.1056/nejmoa051113
  4. Levine Ross L., Wadleigh Martha, Cools Jan, Ebert Benjamin L., Wernig Gerlinde, Huntly Brian J.P., Boggon Titus J., Wlodarska Iwona, Clark Jennifer J., Moore Sandra, Adelsperger Jennifer, Koo Sumin, Lee Jeffrey C., Gabriel Stacey, Mercher Thomas, D’Andrea Alan, Fröhling Stefan, Döhner Konstanze, Marynen Peter, Vandenberghe Peter, Mesa Ruben A., Tefferi Ayalew, Griffin James D., Eck Michael J., Sellers William R., Meyerson Matthew, Golub Todd R., Lee Stephanie J., Gilliland D. Gary, Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis, 10.1016/j.ccr.2005.03.023
  5. Baxter E Joanna, Scott Linda M, Campbell Peter J, East Clare, Fourouclas Nasios, Swanton Soheila, Vassiliou George S, Bench Anthony J, Boyd Elaine M, Curtin Natasha, Scott Mike A, Erber Wendy N, Green Anthony R, Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders, 10.1016/s0140-6736(05)71142-9
  6. Jones A. V., Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders, 10.1182/blood-2005-03-1320
  7. Zhao Runxiang, Xing Shu, Li Zhe, Fu Xueqi, Li Qingshan, Krantz Sanford B., Zhao Zhizhuang Joe, Identification of an Acquired JAK2 Mutation in Polycythemia Vera, 10.1074/jbc.c500138200
  8. Saharinen P., Autoinhibition of Jak2 Tyrosine Kinase Is Dependent on Specific Regions in Its Pseudokinase Domain, 10.1091/mbc.e02-06-0342
  9. Dusa Alexandra, Mouton Céline, Pecquet Christian, Herman Murielle, Constantinescu Stefan N., JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors, 10.1371/journal.pone.0011157
  10. Staerk Judith, Kallin Anders, Demoulin Jean-Baptiste, Vainchenker William, Constantinescu Stefan N., JAK1 and Tyk2 Activation by the Homologous Polycythemia Vera JAK2 V617F Mutation : CROSS-TALK WITH IGF1 RECEPTOR, 10.1074/jbc.c500358200
  11. Lu X., Levine R., Tong W., Wernig G., Pikman Y., Zarnegar S., Gilliland D. G., Lodish H., Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation, 10.1073/pnas.0509714102
  12. Wernig G., Gonneville J. R., Crowley B. J., Rodrigues M. S., Reddy M. M., Hudon H. E., Walz C., Reiter A., Podar K., Royer Y., Constantinescu S. N., Tomasson M. H., Griffin J. D., Gilliland D. G., Sattler M., The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes, 10.1182/blood-2007-07-102186
  13. Teofili L., Martini M., Cenci T., Petrucci G., Torti L., Storti S., Guidi F., Leone G., Larocca L. M., Different STAT-3 and STAT-5 phosphorylation discriminates among Ph-negative chronic myeloproliferative diseases and is independent of the V617F JAK-2 mutation, 10.1182/blood-2007-01-069237
  14. Yan D., Hutchison R. E., Mohi G., Critical requirement for Stat5 in a mouse model of polycythemia vera, 10.1182/blood-2011-03-345215
  15. Walz C., Ahmed W., Lazarides K., Betancur M., Patel N., Hennighausen L., Zaleskas V. M., Van Etten R. A., Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2V617F in mice, 10.1182/blood-2011-12-397554
  16. Olthof Sandra G., Fatrai Szabolcs, Drayer A. Lyndsay, Tyl Monika R., Vellenga Edo, Schuringa Jan Jacob, Downregulation of Signal Transducer and Activator of Transcription 5 (STAT5) in CD34+Cells Promotes Megakaryocytic Development, Whereas Activation of STAT5 Drives Erythropoiesis, 10.1634/stemcells.2007-0899
  17. Chen Edwin, Beer Philip A., Godfrey Anna L., Ortmann Christina A., Li Juan, Costa-Pereira Ana P., Ingle Catherine E., Dermitzakis Emmanouil T., Campbell Peter J., Green Anthony R., Distinct Clinical Phenotypes Associated with JAK2V617F Reflect Differential STAT1 Signaling, 10.1016/j.ccr.2010.10.013
  18. Fialkow P J, Clonal Origin of Human Tumors, 10.1146/annurev.me.30.020179.001031
  19. Jamieson C. H. M., Gotlib J., Durocher J. A., Chao M. P., Mariappan M. R., Lay M., Jones C., Zehnder J. L., Lilleberg S. L., Weissman I. L., The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation, 10.1073/pnas.0601462103
  20. James C., Mazurier F., Dupont S., Chaligne R., Lamrissi-Garcia I., Tulliez M., Lippert E., Mahon F.-X., Pasquet J.-M., Etienne G., Delhommeau F., Giraudier S., Vainchenker W., de Verneuil H., The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity, 10.1182/blood-2008-02-137877
  21. Delhommeau F., Dupont S., Tonetti C., Masse A., Godin I., Couedic J.-P. L., Debili N., Saulnier P., Casadevall N., Vainchenker W., Giraudier S., Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis, 10.1182/blood-2006-03-007146
  22. Lacout C., JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis, 10.1182/blood-2006-02-002030
  23. Wernig G., Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model, 10.1182/blood-2005-12-4824
  24. Zaleskas Virginia M., Krause Daniela S., Lazarides Katherine, Patel Nihal, Hu Yiguo, Li Shaoguang, Van Etten Richard A., Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F, 10.1371/journal.pone.0000018
  25. Shide K, Shimoda H K, Kumano T, Karube K, Kameda T, Takenaka K, Oku S, Abe H, Katayose K S, Kubuki Y, Kusumoto K, Hasuike S, Tahara Y, Nagata K, Matsuda T, Ohshima K, Harada M, Shimoda K, Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F, 10.1038/sj.leu.2405043
  26. Xing S., Wanting T. H., Zhao W., Ma J., Wang S., Xu X., Li Q., Fu X., Xu M., Zhao Z. J., Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice, 10.1182/blood-2007-05-091579
  27. Dominici Massimo, Tadjali Merhdad, Kepes Steven, Allay Esther R., Boyd Kelli, Ney Paul A., Horwitz Edwin, Persons Derek A., Transgenic mice with pancellular enhanced green fluorescent protein expression in primitive hematopoietic cells and all blood cell progeny, 10.1002/gene.20121
  28. Katzav S, EMBO J, 8, 2283 (1989)
  29. Tiedt R., Hao-Shen H., Sobas M. A., Looser R., Dirnhofer S., Schwaller J., Skoda R. C., Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice, 10.1182/blood-2007-08-107748
  30. Akada H., Yan D., Zou H., Fiering S., Hutchison R. E., Mohi M. G., Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease, 10.1182/blood-2009-04-215848
  31. Marty C., Lacout C., Martin A., Hasan S., Jacquot S., Birling M.-C., Vainchenker W., Villeval J.-L., Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice, 10.1182/blood-2009-12-257063
  32. Mullally Ann, Lane Steven W., Ball Brian, Megerdichian Christine, Okabe Rachel, Al-Shahrour Fatima, Paktinat Mahnaz, Haydu J. Erika, Housman Elizabeth, Lord Allegra M., Wernig Gerlinde, Kharas Michael G., Mercher Thomas, Kutok Jeffery L., Gilliland D. Gary, Ebert Benjamin L., Physiological Jak2V617F Expression Causes a Lethal Myeloproliferative Neoplasm with Differential Effects on Hematopoietic Stem and Progenitor Cells, 10.1016/j.ccr.2010.05.015
  33. Li J., Kent D. G., Chen E., Green A. R., Mouse models of myeloproliferative neoplasms: JAK of all grades, 10.1242/dmm.006817
  34. Anand S., Stedham F., Beer P., Gudgin E., Ortmann C. A., Bench A., Erber W., Green A. R., Huntly B. J. P., Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms, 10.1182/blood-2010-12-327593
  35. Ishii Takefumi, Zhao Yan, Sozer Selcuk, Shi Jun, Zhang Wei, Hoffman Ronald, Xu Mingjiang, Behavior of CD34+ cells isolated from patients with polycythemia vera in NOD/SCID mice, 10.1016/j.exphem.2007.07.005
  36. Schuringa Jan Jacob, Chung Ki Young, Morrone Giovanni, Moore Malcolm A.S., Constitutive Activation of STAT5A Promotes Human Hematopoietic Stem Cell Self-Renewal and Erythroid Differentiation, 10.1084/jem.20041024
  37. Wierenga A. T. J., Vellenga E., Schuringa J. J., Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels, 10.1128/mcb.01025-08
  38. Fatrai S., Wierenga A. T. J., Daenen S. M. G. J., Vellenga E., Schuringa J. J., Identification of HIF2  as an important STAT5 target gene in human hematopoietic stem cells, 10.1182/blood-2010-08-303669
  39. Onishi Mayumi, Nosaka Tetsuya, Misawa Kazuhide, Mui Alice L.-F., Gorman Daniel, McMahon Martin, Miyajima Atsushi, Kitamura Toshio, Identification and Characterization of a Constitutively Active STAT5 Mutant That Promotes Cell Proliferation, 10.1128/mcb.18.7.3871
  40. Moucadel Virginie, Constantinescu Stefan N., Differential STAT5 Signaling by Ligand-dependent and Constitutively Active Cytokine Receptors, 10.1074/jbc.m407326200
  41. Girardot M., Pecquet C., Boukour S., Knoops L., Ferrant A., Vainchenker W., Giraudier S., Constantinescu S. N., miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets, 10.1182/blood-2008-06-165985
  42. Wierenga A. T. J., STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBP , 10.1182/blood-2005-11-4608
  43. Essers Marieke A. G., Offner Sandra, Blanco-Bose William E., Waibler Zoe, Kalinke Ulrich, Duchosal Michel A., Trumpp Andreas, IFNα activates dormant haematopoietic stem cells in vivo, 10.1038/nature07815
  44. Baldridge Megan T., King Katherine Y., Boles Nathan C., Weksberg David C., Goodell Margaret A., Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection, 10.1038/nature09135
  45. Uzé G., Schreiber G., Piehler J., Pellegrini S., The Receptor of the Type I Interferon Family, Interferon: The 50th Anniversary ISBN:9783540713289 p.71-95, 10.1007/978-3-540-71329-6_5
  46. Trumpp Andreas, Essers Marieke, Wilson Anne, Awakening dormant haematopoietic stem cells, 10.1038/nri2726
  47. Kiladjian J.-J., Mesa R. A., Hoffman R., The renaissance of interferon therapy for the treatment of myeloid malignancies, 10.1182/blood-2010-08-258772
  48. Tahiliani M., Koh K. P., Shen Y., Pastor W. A., Bandukwala H., Brudno Y., Agarwal S., Iyer L. M., Liu D. R., Aravind L., Rao A., Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1, 10.1126/science.1170116
  49. Delhommeau François, Dupont Sabrina, Valle Véronique Della, James Chloé, Trannoy Severine, Massé Aline, Kosmider Olivier, Le Couedic Jean-Pierre, Robert Fabienne, Alberdi Antonio, Lécluse Yann, Plo Isabelle, Dreyfus François J., Marzac Christophe, Casadevall Nicole, Lacombe Catherine, Romana Serge P., Dessen Philippe, Soulier Jean, Viguié Franck, Fontenay Michaela, Vainchenker William, Bernard Olivier A., Mutation inTET2in Myeloid Cancers, 10.1056/nejmoa0810069
  50. Kiladjian J-J, Massé A, Cassinat B, Mokrani H, Teyssandier I, le Couédic J-P, Cambier N, Almire C, Pronier E, Casadevall N, Vainchenker W, Chomienne C, Delhommeau F, Clonal analysis of erythroid progenitors suggests that pegylated interferon α-2a treatment targets JAK2V617F clones without affecting TET2 mutant cells, 10.1038/leu.2010.120
  51. Challen Grant A., Boles Nathan C., Chambers Stuart M., Goodell Margaret A., Distinct Hematopoietic Stem Cell Subtypes Are Differentially Regulated by TGF-β1, 10.1016/j.stem.2010.02.002
  52. Stein Brady L., Williams Donna M., Rogers Ophelia, Isaacs Mary Ann, Spivak Jerry L., Moliterno Alison R., Disease burden at the progenitor level is a feature of primary myelofibrosis: a multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients, 10.1016/j.exphem.2010.09.008
  53. Rosti Vittorio, Massa Margherita, Vannucchi Alessandro M., Bergamaschi Gaetano, Campanelli Rita, Pecci Alessandro, Viarengo Gianluca, Meli Valentina, Marchetti Monia, Guglielmelli Paola, Bruno Edward, Xu Mingjiang, Hoffman Ronald, Barosi Giovanni, The expression of CXCR4 is down-regulated on the CD34+ cells of patients with myelofibrosis with myeloid metaplasia, 10.1016/j.bcmd.2007.01.003
  54. Sozer Selcuk, Ishii Takefumi, Fiel Maria Isabel, Wang Jiapeng, Wang Xiaoli, Zhang Wei, Godbold Jim, Xu Mingjiang, Hoffman Ronald, Human CD34+ cells are capable of generating normal and JAK2V617F positive endothelial like cells in vivo, 10.1016/j.bcmd.2009.08.005
Bibliographic reference Staerk, Judith ; Constantinescu, Stefan N.. The JAK-STAT pathway and hematopoietic stem cells from the JAK2 V617F perspective. In: JAK-STAT, Vol. 1, no.3, p. 184-190 (2012)
Permanent URL http://hdl.handle.net/2078/122655