Annals of Hematology

, Volume 92, Issue 9, pp 1229–1238 | Cite as

Aberrant expression of signaling proteins in essential thrombocythemia

  • Wuhan Hui
  • Fei Ye
  • Wei Zhang
  • Congyan Liu
  • Miao Cui
  • Wei Li
  • Juan Xu
  • David Y. Zhang
Original Article


Dysregulated expression of signaling proteins may contribute to the pathophysiology of essential thrombocythemia (ET). This study aimed to characterize protein expression in ET and to correlate the dysregulated proteins with phenotypes and prognosis of ET patients. The expression of 128 proteins in peripheral blood neutrophils from 74 ET patients was assessed and compared with those from 29 healthy subjects and 35 polycythemia vera (PV) patients using protein pathway array. Fifteen proteins were differentially expressed between ET patients and normal controls. These dysregulated proteins were involved in the signaling pathways related with apoptosis and inflammation. Our results showed a significant overlap in protein expression between ET patients with JAK2V617F mutation and PV patients. In addition, nine proteins were associated with JAK2V617F mutation status in ET patients. Furthermore, estrogen receptor beta (ERβ) and Stat3 were independent risk factors for subsequent thrombosis during follow-up on multivariable analysis. Our study shows a broad dysregulation of signaling protein in ET patients, suggesting their roles in ET pathogenesis. The expression levels of ERβ and Stat3 could be promising predictors of subsequent thrombosis in ET patients.


Essential thrombocythemia Signaling protein JAK2V617F mutation ERβ Stat3 



We thank Dr. Li Su, Dr. Suigui Wan, Dr. Wanling Sun, Dr. Hong Zhao, and Dr. Bingxin Ji for collecting the samples and clinical information. We thank Dr. Wei Yang and Dr. Fei Yin for the technical support in PPA experiments. This study was supported in part by research funding from Xuan Wu Hospital, Capital Medical University, Beijing, China.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Baxter EJ, Scott LM, Campbell PJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061PubMedGoogle Scholar
  2. 2.
    James C, Ugo V, Le Couedic JP et al (2005) A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 434:1144–1148PubMedCrossRefGoogle Scholar
  3. 3.
    Vannucchi AM, Antonioli E, Guglielmelli P et al (2008) Characteristics and clinical correlates of MPL 515 W > L/K mutation in essential thrombocythemia. Blood 112:844–847PubMedCrossRefGoogle Scholar
  4. 4.
    Zhang DY, Ye F, Gao L et al (2009) Proteomics, pathway array and signaling network-based medicine in cancer. Cell Div 4:20PubMedCrossRefGoogle Scholar
  5. 5.
    Wang D, Ye F, Sun Y et al (2011) Protein signatures for classification and prognosis of gastric cancer a signaling pathway-based approach. Am J Pathol 179:1657–1666PubMedCrossRefGoogle Scholar
  6. 6.
    Wang H, Gillis A, Zhao C et al (2011) Crocidolite asbestos-induced signal pathway dysregulation in mesothelial cells. Mutat Res 723:171–176PubMedCrossRefGoogle Scholar
  7. 7.
    Che Y, Ye F, Xu R et al (2012) Co-expression of XIAP and Cyclin D1 complex correlates with a poorer prognosis in patients with hepatocellular carcinoma. Am J Pathol 180:1798–1807PubMedCrossRefGoogle Scholar
  8. 8.
    Jaffe ES, Harris NL, Stein H, Vardiman JW (2001) International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, LyonGoogle Scholar
  9. 9.
    Tefferi A, Thiele J, Orazi A et al (2007) Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 110:1092–1097PubMedCrossRefGoogle Scholar
  10. 10.
    Bauer S, Abdgawad M, Gunnarsson L et al (2007) Proteinase 3 and CD177 are expressed on the plasma membrane of the same subset of neutrophils. J Leukoc Biol 81:458–464PubMedCrossRefGoogle Scholar
  11. 11.
    Germer S, Holland MJ, Higuchi R (2000) High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res 10:258–266PubMedCrossRefGoogle Scholar
  12. 12.
    Ye F, Che Y, McMillen E et al (2009) The effect of Scutellaria baicalensis on the signaling network in hepatocellular carcinoma cells. Nutr Cancer 61:530–537PubMedCrossRefGoogle Scholar
  13. 13.
    Cortelazzo S, Viero P, Finazzi G et al (1990) Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 8:556–562PubMedGoogle Scholar
  14. 14.
    Chen HY, Yu SL, Chen CH et al (2007) A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med 356:11–20PubMedCrossRefGoogle Scholar
  15. 15.
    Kralovics R, Teo SS, Buser AS et al (2005) Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood 106:3374–3376PubMedCrossRefGoogle Scholar
  16. 16.
    Slezak S, Jin P, Caruccio L et al (2009) Gene and microRNA analysis of neutrophils from patients with polycythemia vera and essential thrombocytosis: down-regulation of micro RNA-1 and -133a. J Transl Med 7:39PubMedCrossRefGoogle Scholar
  17. 17.
    Puigdecanet E, Espinet B, Lozano JJ et al (2008) Gene expression profiling distinguishes JAK2V617F-negative from JAK2V617F-positive patients in essential thrombocythemia. Leukemia 22:1368–1376PubMedCrossRefGoogle Scholar
  18. 18.
    Schwemmers S, Will B, Waller CF et al (2007) JAK2V617F-negative ET patients do not display constitutively active JAK/STAT signaling. Exp Hematol 35:1695–1703PubMedCrossRefGoogle Scholar
  19. 19.
    Takeuchi K, Higuchi T, Yamashita T et al (1999) Chemokine production by human megakaryocytes derived from CD34-positive cord blood cells. Cytokine 11:424–434PubMedCrossRefGoogle Scholar
  20. 20.
    Laubach JP, Fu P, Jiang X et al (2009) Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation. Exp Hematol 37(12):1411–1422PubMedCrossRefGoogle Scholar
  21. 21.
    Karin M, Cao Y, Greten FR et al (2002) NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2:301–310PubMedCrossRefGoogle Scholar
  22. 22.
    Stettner M, Kaulfuss S, Burfeind P et al (2007) The relevance of estrogen receptor-beta expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment. Mol Cancer Ther 6:2626–2633PubMedCrossRefGoogle Scholar
  23. 23.
    Shim GJ, Wang L, Andersson S et al (2003) Disruption of the estrogen receptor beta gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis. Proc Natl Acad Sci USA 100:6694–6699PubMedCrossRefGoogle Scholar
  24. 24.
    Terashita Y, Ishiguro H, Haruki N et al (2004) Excision repair cross complementing 3 expression is involved in patient prognosis and tumor progression in esophageal cancer. Oncol Rep 12:827–831PubMedGoogle Scholar
  25. 25.
    Jost E, do ON, Dahl E et al (2007) Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR/ABL-negative myeloproliferative disorders. Leukemia 21:505–510PubMedCrossRefGoogle Scholar
  26. 26.
    Carobbio A, Antonioli E, Guglielmelli P et al (2008) Leukocytosis and risk stratification assessment in essential thrombocythemia. J Clin Oncol 26:2732–2736PubMedCrossRefGoogle Scholar
  27. 27.
    Palandri F, Polverelli N, Catani L et al (2011) Impact of leukocytosis on thrombotic risk and survival in 532 patients with essential thrombocythemia: a retrospective study. Ann Hematol 90:933–938PubMedCrossRefGoogle Scholar
  28. 28.
    Tefferi A, Gangat N, Wolanskyj A (2007) The interaction between leukocytosis and other risk factors for thrombosis in essential thrombocythemia. Blood 109:4105PubMedCrossRefGoogle Scholar
  29. 29.
    Girodon F, Dutrillaux F, Broseus J et al (2010) Leukocytosis is associated with poor survival but not with increased risk of thrombosis in essential thrombocythemia: a population-based study of 311 patients. Leukemia 24:900–903PubMedCrossRefGoogle Scholar
  30. 30.
    Gangat N, Wolanskyj AP, Schwager SM et al (2009) Leukocytosis at diagnosis and the risk of subsequent thrombosis in patients with low-risk essential thrombocythemia and polycythemia vera. Cancer 115:5740–5745PubMedCrossRefGoogle Scholar
  31. 31.
    Anand S, Stedham F, Gudgin E et al (2011) Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. Blood 118:1610–1621PubMedCrossRefGoogle Scholar
  32. 32.
    Drachman JG, Sabath DF, Fox NE et al (1997) Thrombopoietin signal transduction in purified murine megakaryocytes. Blood 89:483–492PubMedGoogle Scholar
  33. 33.
    Kirito K, Osawa M, Morita H et al (2002) A functional role of Stat3 in vivo megakaryopoiesis. Blood 99:3220–3227PubMedCrossRefGoogle Scholar
  34. 34.
    Jayachandran M, Preston CC, Hunter LW et al (2010) Loss of estrogen receptor beta decreases mitochondrial energetic potential and increases thrombogenicity of platelets in aged female mice. Age (Dordr) 32:109–121CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Hematology, Xuan Wu HospitalCapital Medical UniversityBeijingChina
  2. 2.Department of PathologyMount Sinai School of MedicineNew YorkUSA
  3. 3.Department of General Surgery, First HospitalJilin UniversityChangchunChina

Personalised recommendations