Reader TTS

ABSTRACT JAK2V617F is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in

p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/F3-EPOR cells and _ex

vivo_ cultured CD34+ cells from MPN patients, we demonstrate that expression of JAK2V617F affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these

cells, due to an increased translation of _MDM2_ mRNA. Accumulation of the La autoantigen, which interacts with _MDM2_ mRNA and promotes its translation, was responsible for the increase in

MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA

damage and the cytokine-dependence of Ba/F3-EPOR-JAK2V617F cells. Altogether, these data indicate that the JAK2V617F mutation affects p53 response to DNA damage through the upregulation of

La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of JAK2V617F MPN and might have a role in disease

progression. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe

to this journal Receive 50 print issues and online access $259.00 per year only $5.18 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF

Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact

customer support SIMILAR CONTENT BEING VIEWED BY OTHERS YBX1 MEDIATES TRANSLATION OF ONCOGENIC TRANSCRIPTS TO CONTROL CELL COMPETITION IN AML Article Open access 31 August 2021 FBXO21

MEDIATED DEGRADATION OF P85Α REGULATES PROLIFERATION AND SURVIVAL OF ACUTE MYELOID LEUKEMIA Article Open access 09 September 2023 MAPK-NEGATIVE FEEDBACK REGULATION CONFERS DEPENDENCE TO

JAK2V617F SIGNALING Article 10 July 2023 REFERENCES * Akyuz N, Boehden GS, Susse S, Rimek A, Preuss U, Scheidtmann KH _et al_. (2002). DNA substrate dependence of p53-mediated regulation of

double-strand break repair. _Mol Cell Biol_ 22: 6306–6317. Article  CAS  Google Scholar  * Barosi G, Ambrosetti A, Finelli C, Grossi A, Leoni P, Liberato NL _et al_. (1999). The Italian

Consensus Conference on diagnostic criteria for myelofibrosis with myeloid metaplasia. _Br J Haematol_ 104: 730–737. Article  CAS  Google Scholar  * Baxter EJ, Scott LM, Campbell PJ, East C,

Fourouclas N, Swanton S _et al_. (2005). Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. _Lancet_ 365: 1054–1061. Article  CAS  Google Scholar  *

Berthebaud M, Riviere C, Jarrier P, Foudi A, Zhang Y, Compagno D _et al_. (2005). RGS16 is a negative regulator of SDF-1-CXCR4 signaling in megakaryocytes. _Blood_ 106: 2962–2968. Article 

CAS  Google Scholar  * Bertrand P, Saintigny Y, Lopez BS . (2004). p53's double life: transactivation-independent repression of homologous recombination. _Trends Genet_ 20: 235–243.

Article  CAS  Google Scholar  * Candeias MM, Malbert-Colas L, Powell DJ, Daskalogianni C, Maslon MM, Naski N _et al_. (2008). p53 mRNA controls p53 activity by managing Mdm2 functions. _Nat

Cell Biol_ 10: 1098–1105. Article  CAS  Google Scholar  * Capoulade C, Bressac-de Paillerets B, Lefrere I, Ronsin M, Feunteun J, Tursz T _et al_. (1998). Overexpression of MDM2, due to

enhanced translation, results in inactivation of wild-type p53 in Burkitt's lymphoma cells. _Oncogene_ 16: 1603–1610. Article  CAS  Google Scholar  * Cummings WJ, Yabuki M, Ordinario

EC, Bednarski DW, Quay S, Maizels N . (2007). Chromatin structure regulates gene conversion. _PLoS Biol_ 5: e246. Article  Google Scholar  * Dawson MA, Bannister AJ, Gottgens B, Foster SD,

Bartke T, Green AR _et al_. (2009). JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. _Nature_ 461: 819–822. Article  CAS  Google Scholar  * Faderl S, Kantarjian HM,

Estey E, Manshouri T, Chan CY, Rahman Elsaied A _et al_. (2000). The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM-2 protein expression in adult acute myelogenous

leukemia. _Cancer_ 89: 1976–1982. Article  CAS  Google Scholar  * Feinstein E, Cimino G, Gale RP, Alimena G, Berthier R, Kishi K _et al_. (1991). p53 in chronic myelogenous leukemia in acute

phase. _Proc Natl Acad Sci USA_ 88: 6293–6297. Article  CAS  Google Scholar  * Freedman DA, Wu L, Levine AJ . (1999). Functions of the MDM2 oncoprotein. _Cell Mol Life Sci_ 55: 96–107.

Article  CAS  Google Scholar  * Gaidano G, Pastore C, Santini V, Nomdedeu J, Gamberi B, Capello D _et al_. (1997). Genetic lesions associated with blastic transformation of polycythemia vera

and essential thrombocythemia. _Genes Chromosomes Cancer_ 19: 250–255. Article  CAS  Google Scholar  * Gangat N, Strand J, Lasho TL, Finke CM, Knudson RA, Pardanani A _et al_. (2007).

Cytogenetic studies at diagnosis in polycythemia vera: clinical and JAK2V617F allele burden correlates. _Eur J Haematol_ 80: 197–200. Article  Google Scholar  * Goetz AW, van der Kuip H,

Maya R, Oren M, Aulitzky WE . (2001). Requirement for Mdm2 in the survival effects of Bcr-Abl and interleukin 3 in hematopoietic cells. _Cancer Res_ 61: 7635–7641. CAS  PubMed  Google

Scholar  * Hernandez-Boussard T, Rodriguez-Tome P, Montesano R, Hainaut P . (1999). IARC p53 mutation database: a relational database to compile and analyze p53 mutations in human tumors and

cell lines. International Agency for Research on Cancer. _Hum Mutat_ 14: 1–8. Article  CAS  Google Scholar  * Holcik M, Korneluk RG . (2000). Functional characterization of the X-linked

inhibitor of apoptosis (XIAP) internal ribosome entry site element: role of La autoantigen in XIAP translation. _Mol Cell Biol_ 20: 4648–4657. Article  CAS  Google Scholar  * Ishiguro K,

Shyam K, Penketh PG, Sartorelli AC . (2005). Role of O6-alkylguanine-DNA alkyltransferase in the cytotoxic activity of cloretazine. _Mol Cancer Ther_ 4: 1755–1763. Article  CAS  Google

Scholar  * James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C _et al_. (2005). A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.

_Nature_ 434: 1144–1148. Article  CAS  Google Scholar  * Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD, Pearson RB . (2007). Coordinate regulation of ribosome biogenesis and function

by the ribosomal protein S6 kinase, a key mediator of mTOR function. _Growth Factors_ 25: 209–226. Article  CAS  Google Scholar  * Kantarjian HM, Keating MJ, Talpaz M, Walters RS, Smith TL,

Cork A _et al_. (1987). Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. _Am J Med_ 83: 445–454. Article  CAS  Google Scholar  * Kawamata N, Ogawa S, Yamamoto G,

Lehmann S, Levine RL, Pikman Y _et al_. (2008). Genetic profiling of myeloproliferative disorders by single-nucleotide polymorphism oligonucleotide microarray. _Exp Hematol_ 36: 1471–1479.

Article  CAS  Google Scholar  * Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR _et al_. (2005). A gain-of-function mutation of JAK2 in myeloproliferative disorders. _N Engl

J Med_ 352: 1779–1790. Article  CAS  Google Scholar  * Lacout C, Pisani DF, Tulliez M, Gachelin FM, Vainchenker W, Villeval JL . (2006). JAK2V617F expression in murine hematopoietic cells

leads to MPD mimicking human PV with secondary myelofibrosis. _Blood_ 108: 1652–1660. Article  CAS  Google Scholar  * Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ _et al_.

(2005). Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. _Cancer Cell_ 7: 387–397. Article  CAS 

Google Scholar  * Liu R, Liu CB, Mohi MG, Arai K, Watanabe S . (2000). Analysis of mechanisms involved in the prevention of gamma irradiation-induced apoptosis by hGM-CSF. _Oncogene_ 19:

571–579. Article  CAS  Google Scholar  * Maetens M, Doumont G, Clercq SD, Francoz S, Froment P, Bellefroid E _et al_. (2007). Distinct roles of Mdm2 and Mdm4 in red cell production. _Blood_

109: 2630–2633. Article  CAS  Google Scholar  * Mendrysa SM, McElwee MK, Perry ME . (2001). Characterization of the 5′ and 3′ untranslated regions in murine mdm2 mRNAs. _Gene_ 264: 139–146.

Article  CAS  Google Scholar  * Michiels JJ, Barbui T, Finazzi G, Fuchtman SM, Kutti J, Rain JD _et al_. (2000). Diagnosis and treatment of polycythemia vera and possible future study

designs of the PVSG. _Leuk Lymphoma_ 36: 239–253. Article  CAS  Google Scholar  * Perrotti D, Neviani P . (2007). From mRNA metabolism to cancer therapy: chronic myelogenous leukemia shows

the way. _Clin Cancer Res_ 13: 1638–1642. Article  CAS  Google Scholar  * Plo I, Nakatake M, Malivert L, de Villartay JP, Giraudier S, Villeval JL _et al_. (2008). JAK2 stimulates homologous

recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. _Blood_ 112: 1402–1412. Article  CAS  Google Scholar  * Reilly JT .

(2005). Cytogenetic and molecular genetic abnormalities in agnogenic myeloid metaplasia. _Semin Oncol_ 32: 359–364. Article  CAS  Google Scholar  * Scolan EL, Wendling F, Barnache S, Denis

N, Tulliez M, Vainchenker W _et al_. (2001). Germ-line deletion of p53 reveals a multistage tumor progression in spi-1/PU.1 transgenic proerythroblasts. _Oncogene_ 20: 5484–5492. Article 

CAS  Google Scholar  * Seliger B, Papadileris S, Vogel D, Hess G, Brendel C, Storkel S _et al_. (1996). Analysis of the p53 and MDM-2 gene in acute myeloid leukemia. _Eur J Haematol_ 57:

230–240. Article  CAS  Google Scholar  * Sengupta S, Linke SP, Pedeux R, Yang Q, Farnsworth J, Garfield SH _et al_. (2003). BLM helicase-dependent transport of p53 to sites of stalled DNA

replication forks modulates homologous recombination. _Embo J_ 22: 1210–1222. Article  CAS  Google Scholar  * Shangary S, Wang S . (2009). Small-molecule inhibitors of the MDM2-p53

protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. _Annu Rev Pharmacol Toxicol_ 49: 223–241. Article  CAS  Google Scholar  * Shide K, Shimoda HK,

Kumano T, Karube K, Kameda T, Takenaka K _et al_. (2008). Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. _Leukemia_ 22: 87–95. Article  CAS  Google Scholar  *

Sieff CA, Yang J, Merida-Long LB, Lodish HF . (2010). Pathogenesis of the erythroid failure in Diamond Blackfan anaemia. _Br J Haematol_ 148: 611–622. Article  CAS  Google Scholar  * Smith

ML, Seo YR . (2002). p53 regulation of DNA excision repair pathways. _Mutagenesis_ 17: 149–156. Article  CAS  Google Scholar  * Takagi M, Absalon MJ, McLure KG, Kastan MB . (2005).

Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. _Cell_ 123: 49–63. Article  CAS  Google Scholar  * Tefferi A, Sirhan S, Sun Y, Lasho T,

Finke CM, Weisberger J _et al_. (2009). Oligonucleotide array CGH studies in myeloproliferative neoplasms: comparison with JAK2V617F mutational status and conventional chromosome analysis.

_Leuk Res_ 33: 662–664. Article  CAS  Google Scholar  * Tiedt R, Hao-Shen H, Sobas MA, Looser R, Dirnhofer S, Schwaller J _et al_. (2008). Ratio of mutant JAK2-V617F to wild type JAK2

determines the MPD phenotypes in transgenic mice. _Blood_ 111: 3931–3940. Article  CAS  Google Scholar  * Trotta R, Vignudelli T, Candini O, Intine RV, Pecorari L, Guerzoni C _et al_.

(2003). BCR/ABL activates mdm2 mRNA translation via the La antigen. _Cancer Cell_ 3: 145–160. Article  CAS  Google Scholar  * Tsurumi S, Nakamura Y, Maki K, Omine M, Fujita K, Okamura T _et

al_. (2002). N-ras and p53 gene mutations in Japanese patients with myeloproliferative disorders. _Am J Hematol_ 71: 131–133. Article  CAS  Google Scholar  * Vassilev LT, Vu BT, Graves B,

Carvajal D, Podlaski F, Filipovic Z _et al_. (2004). _in vivo_ activation of the p53 pathway by small-molecule antagonists of MDM2. _Science_ 303: 844–848. Article  CAS  Google Scholar  *

Wernig G, Mercher T, Okabe R, Levine RL, Lee BH, Gilliland DG . (2006). Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow

transplant model. _Blood_ 107: 4274–4281. Article  CAS  Google Scholar  * Wong KS, Li YJ, Howard J, Ben-David Y . (1999). Loss of p53 in F-MuLV induced-erythroleukemias accelerates the

acquisition of mutational events that confers immortality and growth factor independence. _Oncogene_ 18: 5525–5534. Article  CAS  Google Scholar  * Zhao R, Follows GA, Beer PA, Scott LM,

Huntly BJ, Green AR _et al_. (2008). Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders. _N Engl J Med_ 359: 2778–2789. Article  CAS  Google Scholar  * Zhou M, Gu

L, Abshire TC, Homans A, Billett AL, Yeager AM _et al_. (2000). Incidence and prognostic significance of MDM2 oncoprotein overexpression in relapsed childhood acute lymphoblastic leukemia.

_Leukemia_ 14: 61–67. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank all the patients and the controls who participated in the study, and AstraZeneca for the

gift of the JAK2 inhibitor (AZD1480). We are grateful to Drs LT Vassilev and R Fahraeus for fruitful discussion. We also thank Dr F Wendling for critical reading of the manuscript. This work

was supported by grants from the Ligue Nationale Contre le Cancer (équipe labellisée 2007–2010 et 2010–2012), INCa (projets libres 2007) and INSERM. IP was a recipient from INCA, MN from

the Ligue Nationale Contre le Cancer, BMM from the Fondation pour la Recherche Médicale. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * INSERM UMR 1009, Villejuif, France M Nakatake, B

Monte-Mor, N Debili, N Casadevall, V Ribrag, E Solary, W Vainchenker & I Plo * Université Paris XI, UMR1009, Institut Gustave Roussy, Villejuif, France M Nakatake, B Monte-Mor, N Debili,

 V Ribrag, E Solary, W Vainchenker & I Plo * Institut Gustave Roussy, Villejuif, France M Nakatake, B Monte-Mor, N Debili, V Ribrag, E Solary, W Vainchenker & I Plo * AP-HP,

Laboratoire d’hématologie-Hôpital Saint Antoine, Paris, France N Casadevall * Université Pierre et Marie Curie, Paris VI, France N Casadevall Authors * M Nakatake View author publications

You can also search for this author inPubMed Google Scholar * B Monte-Mor View author publications You can also search for this author inPubMed Google Scholar * N Debili View author

publications You can also search for this author inPubMed Google Scholar * N Casadevall View author publications You can also search for this author inPubMed Google Scholar * V Ribrag View

author publications You can also search for this author inPubMed Google Scholar * E Solary View author publications You can also search for this author inPubMed Google Scholar * W

Vainchenker View author publications You can also search for this author inPubMed Google Scholar * I Plo View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to I Plo. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information

accompanies the paper on the Oncogene website SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION (DOC 171 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Nakatake, M., Monte-Mor, B., Debili, N. _et al._ JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms. _Oncogene_ 31,

1323–1333 (2012). https://doi.org/10.1038/onc.2011.313 Download citation * Received: 10 January 2011 * Revised: 17 June 2011 * Accepted: 18 June 2011 * Published: 25 July 2011 * Issue Date:

08 March 2012 * DOI: https://doi.org/10.1038/onc.2011.313 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable

link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * JAK2V617F * p53 * MDM2 * La protein *

myeloproliferative neoplasms