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Leukemia
  • Original Article
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Chronic Myeloproliferative Disorders

The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F

Leukemiavolume 22, pages740–747 (2008)Cite this article

Abstract

We investigated the activity of ITF2357, a novel histone deacetylase inhibitor (HDACi) with antitumor activity, on cells carrying the JAK2V617F mutation obtained from polycythemia vera (PV) and essential thrombocythemia (ET) patients as well as the HEL cell line. The clonogenic activity of JAK2V617F mutated cells was inhibited by low concentrations of ITF2357 (IC50 0.001–0.01 μM), 100- to 250-fold lower than required to inhibit growth of normal or tumor cells lacking this mutation. Under these conditions, ITF2357 allowed a seven fold increase in the outgrowth of unmutated over mutated colonies. By western blotting we showed that in HEL cells, ITF2357 led to the disappearance of total and phosphorylated JAK2V617F as well as pSTAT5 and pSTAT3, but it did not affect the wild-type JAK2 or STAT proteins in the control K562 cell line. By real-time PCR, we showed that, upon exposure to ITF2357, JAK2V617F mRNA was not modified in granulocytes from PV patients while the expression of the PRV-1 gene, a known target of JAK2, was rapidly downmodulated. Altogether, the data presented suggest that ITF2357 inhibits proliferation of cells bearing the JAK2V617F mutation through a specific downmodulation of the JAK2V617F protein and inhibition of its downstream signaling.

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References

  1. Tefferi A, Barbui T . bcr/abl-negative, classic myeloproliferative disorders: diagnosis and treatment.Mayo Clin Proc 2005;80: 1220–1232.

    Article PubMed  Google Scholar 

  2. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Awanton Set al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.Lancet 2005;365: 1054–1061.

    Article CAS PubMed  Google Scholar 

  3. James C, Ugo V, Le Couedic JP, Le Couedic JP, Staerk J, Delhommeau Fet al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature 2005;434: 1144–1148.

    Article CAS PubMed  Google Scholar 

  4. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJet al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.Cancer Cell 2005;7: 387–397.

    Article CAS PubMed  Google Scholar 

  5. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JRet al. A gain-of-function mutation of JAK2 in myeloproliferative disorders.N Engl J Med 2005;352: 1779–1790.

    Article CAS PubMed  Google Scholar 

  6. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MRet al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.N Engl J Med 2007;356: 459–468.

    Article CAS PubMed PubMed Central  Google Scholar 

  7. Prchal JF, Axelrad AA . Letter: bone-marrow responses in polycythemia vera.N Engl J Med 1974;290: 1382.

    CAS PubMed  Google Scholar 

  8. Ihle JN, Gilliland DG . Jak2: normal function and role in hematopoietic disorders.Curr Opin Genet Dev 2007;17: 8–14.

    Article CAS PubMed  Google Scholar 

  9. Vainchenker W, Constantinescu SN . A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases.Hematology Am Soc Hematol Educ Program 2005, 195–200.

    Article  Google Scholar 

  10. Kaushansky K . On the molecular origins of the chronic myeloproliferative disorders: it all makes sense.Hematology Am Soc Hematol Educ Program 2005, 533–537.

    Article  Google Scholar 

  11. Jones AV, Silver RT, Waghorn K, Curtis C, Kreil S, Zoi Ket al. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha.Blood 2006;107: 3339–3341.

    Article CAS PubMed  Google Scholar 

  12. Li Z, Xu M, Xing S, Ho WT, Ishii T, Li Qet al. Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth.J Biol Chem 2007;282: 3428–3432.

    Article CAS PubMed  Google Scholar 

  13. Gaikwad A, Verstovsek S, Yoon D, Chang KT, Manshouri T, Nussenzveig Ret al. Imatinib effect on growth and signal transduction in polycythemia vera.Exp Hematol 2007;35: 931–938.

    Article CAS PubMed  Google Scholar 

  14. Lindemann RK, Gabrielli B, Johnstone RW . Histone-deacetylase inhibitors for the treatment of cancer.Cell Cycle 2004;3: 779–788.

    Article CAS PubMed  Google Scholar 

  15. Mehnert JM, Kelly WK . Histone deacetylase inhibitors: biology and mechanism of action.Cancer J 2007;13: 23–29.

    Article CAS PubMed  Google Scholar 

  16. Johnstone RW, Licht JD . Histone deacetylase inhibitors in cancer therapy: is transcription the primary target?Cancer Cell 2003;4: 13–18.

    Article CAS PubMed  Google Scholar 

  17. Liu T, Kuljaca S, Tee A, Marshall GM . Histone deacetylase inhibitors: multifunctional anticancer agents.Cancer Treat Rev 2006;32: 157–165.

    Article PubMed  Google Scholar 

  18. Riester D, Hildmann C, Schwienhorst A . Histone deacetylase inhibitors—turning epigenic mechanisms of gene regulation into tools of therapeutic intervention in malignant and other diseases.Appl Microbiol Biotechnol 2007;75: 499–514.

    Article CAS PubMed  Google Scholar 

  19. Golay J, Cuppini L, Leoni F, Micò C, Barbui V, Domenghini Met al. The histone deacetylase inhibitor ITF2357 has anti-leukemic activityin vitro andin vivo and inhibits IL-6 and VEGF production by stromal cells.Leukemia 2007;21: 1892–1900.

    Article CAS PubMed  Google Scholar 

  20. O'Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli Bet al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies.J Clin Oncol 2006;24: 166–173.

    Article CAS PubMed  Google Scholar 

  21. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani Pet al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokinesin vitro and systemic inflammationin vivo.Mol Med 2005;11: 1–15.

    Article CAS PubMed PubMed Central  Google Scholar 

  22. Michiels JJ, De Raeve H, Berneman Z, Van Bockstaele D, Hebeda K, Lam Ket al. The 2001 World Health Organization and updated European clinical and pathological criteria for the diagnosis, classification, and staging of the Philadelphia chromosome-negative chronic myeloproliferative disorders.Semin Thromb Hemost 2006;32: 307–340.

    Article PubMed  Google Scholar 

  23. Goerttler PS, Steimle C, Marz E, Johansson PL, Andreasson B, Griesshammer Met al. The Jak2V617F mutation, PRV-1 overexpression, and EEC formation define a similar cohort of MPD patients.Blood 2005;106: 2862–2864.

    Article CAS PubMed  Google Scholar 

  24. Schmid I, Ferbas J, Uittenbogaart CH, Giorgi JV . Flow cytometric analysis of live cell proliferation and phenotype in populations with low viability.Cytometry 1999;35: 64–74.

    Article CAS PubMed  Google Scholar 

  25. Spinelli O, Giussani U, Borleri G, Lazzari M, Michelato A, Dotti Get al. Need for an accurate molecular diagnosis to assess the donor origin of leukemia relapse after allogeneic stem cell transplantation.Haematologica 2000;85: 1153–1157.

    CAS PubMed  Google Scholar 

  26. Bettinotti MP, Olsen A, Stroncek D . The use of bioinformatics to identify the genomic structure of the gene that encodes neutrophil antigen NB1, CD177.Clin Immunol 2002;102: 138–144.

    Article CAS PubMed  Google Scholar 

  27. Gabert J, Beillard E, Van der Velden VH, Bi W, Grimwade D, Pallisgaard Net al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program.Leukemia 2003;17: 2318–2357.

    Article CAS PubMed  Google Scholar 

  28. Cittera E, Onofri C, D'Apolito M, Cartron G, Cazzaniga G, Zelante Let al. Rituximab induces different but overlapping sets of genes in human B-lymphoma cell lines.Cancer Immunol Immunother 2005;54: 273–286.

    Article CAS PubMed  Google Scholar 

  29. Klippel S, Strunck E, Busse CE, Behringer D, Pahl HL . Biochemical characterization of PRV-1, a novel hematopoietic cell surface receptor, which is overexpressed in polycythemia rubra vera.Blood 2002;100: 2441–2448.

    Article CAS PubMed  Google Scholar 

  30. Tefferi A, Sirhan S, Lasho TL, Schwager SM, Li CY, Dingli Det al. Concomitant neutrophil JAK2 mutation screening and PRV-1 expression analysis in myeloproliferative disorders and secondary polycythaemia.Br J Haematol 2005;131: 166–171.

    Article CAS PubMed  Google Scholar 

  31. Samanta AK, Lin H, Sun T, Kantarjian H, Arlinghaus RB . Janus kinase 2: a critical target in chronic myelogenous leukemia.Cancer Res 2006;66: 6468–6472.

    Article CAS PubMed  Google Scholar 

  32. Lin TS, Mahajan S, Frank DA . STAT signaling in the pathogenesis and treatment of leukemias.Oncogene 2000;19: 2496–2504.

    Article CAS PubMed  Google Scholar 

  33. Carta S, Tassi S, Semino C, Fossati G, Mascagni P, Dinarello CAet al. Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules.Blood 2006;108: 1618–1626.

    Article CAS PubMed PubMed Central  Google Scholar 

  34. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo Fet al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors.J Biol Chem 2005;280: 26729–26734.

    Article CAS PubMed  Google Scholar 

  35. Citri A, Harari D, Shohat G, Ramakrishnan P, Gan J, Lavi Set al. Hsp90 recognizes a common surface on client kinases.J Biol Chem 2006;281: 14361–14369.

    Article CAS PubMed  Google Scholar 

  36. George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo Fet al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3.Blood 2005;105: 1768–1776.

    Article CAS PubMed  Google Scholar 

  37. Shang L, Tomasi TB . The heat shock protein 90-CDC37 chaperone complex is required for signaling by types I and II interferons.J Biol Chem 2006;281: 1876–1884.

    Article CAS PubMed  Google Scholar 

  38. Bolden JE, Peart MJ, Johnstone RW . Anticancer activities of histone deacetylase inhibitors.Nat Rev Drug Discov 2006;5: 769–784.

    Article CAS PubMed  Google Scholar 

  39. Dokmanovic M, Marks PA . Prospects: histone deacetylase inhibitors.J Cell Biochem 2005;96: 293–304.

    Article CAS PubMed  Google Scholar 

  40. Ali S, Nouhi Z, Chughtai N . SHP-2 regulates SOCS-1-mediated Janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor.J Biol Chem 2003;278: 52021–52031.

    Article CAS PubMed  Google Scholar 

  41. Walz C, Crowley BJ, Hudon HE, Gramlich JL, Neuberg DS, Podar Ket al. Activated Jak2 with the V617F point mutation promotes G1/S phase transition.J Biol Chem 2006;281: 18177–18183.

    Article CAS PubMed  Google Scholar 

  42. Mesa RA, Tefferi A, Lasho TS, Loegering D, McClure RF, Powell HLet al. Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia.Leukemia 2006;20: 1800–1808.

    Article CAS PubMed  Google Scholar 

  43. Garcon L, Rivat C, James C, Lacout C, Camara-Clayette V, Ugo Vet al. Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells.Blood 2006;108: 1551–1554.

    Article CAS PubMed  Google Scholar 

  44. Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha Get al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations.Leukemia 2007;21: 1658–1668.

    Article CAS PubMed  Google Scholar 

  45. Mnjoyan Z, Yoon D, Li J, Delhommeau F, Afshar-Kharghan V . The effect of the JAK2 V617F mutation on PRV-1 expression.Haematologica 2006;91: 411–412.

    CAS PubMed  Google Scholar 

  46. Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono Cet al. Efficacy and safety of low-dose aspirin in polycythemia vera.N Engl J Med 2004;350: 114–124.

    Article CAS PubMed  Google Scholar 

  47. Sterkers Y, Preudhomme C, Lai JL, Demory JL, Caulier MT, Wattel Eet al. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion.Blood 1998;91: 616–622.

    CAS PubMed  Google Scholar 

  48. Finazzi G, Caruso V, Marchioli R, Capnist G, Chisesi T, Finelli Cet al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study.Blood 2005;105: 2664–2670.

    Article CAS PubMed  Google Scholar 

  49. Spivak JL, Barosi G, Tognoni G, Barbui T, Finazzi G, Marchioli Ret al. Chronic myeloproliferative disorders.Hematology Am Soc Hematol Educ Program 2003, 200–224.

    Article  Google Scholar 

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Acknowledgements

This study was financially supported in part by research funding from AIRC (Associazione Italiana Ricerca sul Cancro), Associazione Italiana Contro le Leucemie e i Linfomi (AIL), Sezione Paolo Belli, Bergamo, Italy and by a grant from the National Cancer Institute to the Myeloproliferative Disorders Research Consortium (MPD-RC).

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Authors and Affiliations

  1. Hematology Unit, Ospedali Riuniti, Bergamo, Italy

    V Guerini, V Barbui, O Spinelli, A Salvi, C Dellacasa, A Carobbio, M Introna, T Barbui, J Golay & A Rambaldi

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  1. V Guerini

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  2. V Barbui

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  3. O Spinelli

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  4. A Salvi

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Correspondence toA Rambaldi.

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Guerini, V., Barbui, V., Spinelli, O.et al. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F.Leukemia22, 740–747 (2008). https://doi.org/10.1038/sj.leu.2405049

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