Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Methylated Alteration of SHP1 Complements Mutation of JAK2 Tyrosine Kinase in Patients with Myeloproliferative Neoplasm

  • Yang, Jun-Jun (Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University) ;
  • Chen, Hui (Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University) ;
  • Zheng, Xiao-Qun (Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University) ;
  • Li, Hai-Ying (Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University) ;
  • Wu, Jian-Bo (Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University) ;
  • Tang, Li-Yuan (Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University) ;
  • Gao, Shen-Meng (Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University)
  • Published : 2015.04.03
Download PDF
⟨ Previous Next ⟩

Abstract

SHP1 negatively regulates the Janus kinase 2/signal transducer and activator of transcription (JAK2/STAT) signaling pathway, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia. Promoter hypermethylation resulting in epigenetic inactivation of SHP1 has been reported in myelomas, leukemias and other cancers. However, whether SHP1 hypermethylation occurs in MPNs, especially in Chinese patients, has remained unclear. Here, we report that aberrant hypermethylation of SHP1 was observed in several leukemic cell lines and bone marrow mononuclear cells from MPN patients. About 51 of 118 (43.2%) MPN patients including 23 of 50 (46%) polycythaemia vera patients, 20 of 50 (40%) essential thrombocythaemia and 8 of 18 (44.4%) idiopathic myelofibrosis showed hypermethylation by methylation-specific polymerase chain reaction. However, SHP1 methylation was not measured in 20 healthy volunteers. Hypermethylation of SHP1 was found in MPN patients with both positive (34/81, 42%) and negative (17/37, 45.9%) JAK2V617F mutation. The levels of SHP1 mRNA were significantly lower in hypermethylated samples than unmethylated samples, suggesting SHP1 may be epigenetically inactivated in MPN patients. Furthermore, treatment with 5-aza-2'-deoxycytidine (AZA) in K562 cells showing hypermethylation of SHP1 led to progressive demethylation of SHP1, with consequently increased reexpression of SHP1. Meanwhile, phosphorylated JAK2 and STAT3 were progressively reduced. Finally, AZA increased the expression of SHP1 in primary MPN cells with hypermethylation of SHP1. Therefore, our data suggest that epigenetic inactivation of SHP1 contributes to the constitutive activation of JAK2/STAT signaling. Restoration of SHP1 expression by AZA may contribute to clinical treatment for MPN patients.

Keywords

References

  1. Benekli M, Baer MR, Baumann H, et al (2003). Signal transducer and activator of transcription proteins in leukemias. Blood, 101, 2940-54. https://doi.org/10.1182/blood-2002-04-1204
  2. Capello D, Deambrogi C, Rossi D, et al (2008). Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia-negative chronic myeloproliferative disorders. Br J Haematol, 141, 504-11. https://doi.org/10.1111/j.1365-2141.2008.07072.x
  3. Chim CS, Fung TK, Cheung WC, et al (2004). SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood, 103, 4630-5. https://doi.org/10.1182/blood-2003-06-2007
  4. Gao SM, Chen CQ, Wang LY, et al (2013). Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms. Exp Hematol, 41, 261-70. https://doi.org/10.1016/j.exphem.2012.10.012
  5. Hookham MB, Elliott J, Suessmuth Y, et al (2007). The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3. Blood, 109, 4924-9. https://doi.org/10.1182/blood-2006-08-039735
  6. James C, Ugo V, Le Couedic JP, et al (2005). A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature, 434, 1144-8. https://doi.org/10.1038/nature03546
  7. 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, 505-10. https://doi.org/10.1038/sj.leu.2404513
  8. Khoury JD, Rassidakis GZ, Medeiros LJ, et al (2004). Methylation of SHP1 gene and loss of SHP1 protein expression are frequent in systemic anaplastic large cell lymphoma. Blood, 104, 1580-1. https://doi.org/10.1182/blood-2004-03-1151
  9. Kumagai C, Kalman B, Middleton FA, et al (2012). Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. J Neuroimmunol, 246, 51-7. https://doi.org/10.1016/j.jneuroim.2012.03.003
  10. Levine RL, Wadleigh M, Cools J, et al (2005). Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell, 7, 387-97. https://doi.org/10.1016/j.ccr.2005.03.023
  11. Li LC, Dahiya R (2002). MethPrimer: designing primers for methylation PCRs. Bioinformatics, 18, 1427-31. https://doi.org/10.1093/bioinformatics/18.11.1427
  12. Nakase K, Cheng J, Zhu Q, et al (2009). Mechanisms of SHP-1 P2 promoter regulation in hematopoietic cells and its silencing in HTLV-1-transformed T cells. J Leukoc Biol, 85, 165-74.
  13. Oh ST, Simonds EF, Jones C, et al (2010). Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood, 116, 988-92. https://doi.org/10.1182/blood-2010-02-270108
  14. Oka T, Ouchida M, Koyama M, et al (2002). Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res, 62, 6390-4.
  15. Pardanani A, Gotlib JR, Jamieson C, et al (2011). Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol, 29, 789-96. https://doi.org/10.1200/JCO.2010.32.8021
  16. Pardanani AD, Levine RL, Lasho T, et al (2006). MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood, 108, 3472-6. https://doi.org/10.1182/blood-2006-04-018879
  17. Pietra D, Li S, Brisci A, et al (2008). Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood, 111, 1686-9.
  18. Shen SH, Bastien L, Posner BI, et al (1991). A protein-tyrosine phosphatase with sequence similarity to the SH2 domain of the protein-tyrosine kinases. Nature, 352, 736-9. https://doi.org/10.1038/352736a0
  19. Tefferi A, Vainchenker W (2011). Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol, 29, 573-82. https://doi.org/10.1200/JCO.2010.29.8711
  20. Tefferi A, Vardiman JW (2008). Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia, 22, 14-22. https://doi.org/10.1038/sj.leu.2404955
  21. Tyner JW, Bumm TG, Deininger J, et al (2010). CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood, 115, 5232-40. https://doi.org/10.1182/blood-2009-05-223727
  22. Verstovsek S, Kantarjian HM, Estrov Z, et al (2012a). Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood, 120, 1202-9. https://doi.org/10.1182/blood-2012-02-414631
  23. Verstovsek S, Mesa RA, Gotlib J, et al (2012b). A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med, 366, 799-807. https://doi.org/10.1056/NEJMoa1110557
  24. Wang J, Xu Z, Liu L, et al (2013). JAK2V617F allele burden, JAK2 46/1 haplotype and clinical features of Chinese with myeloproliferative neoplasms. Leukemia, 27, 1763-7 https://doi.org/10.1038/leu.2013.21
  25. Wang Y, Fiskus W, Chong DG, et al (2009). Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood, 114, 5024-33. https://doi.org/10.1182/blood-2009-05-222133
  26. Witkiewicz A, Raghunath P, Wasik A, et al (2007). Loss of SHP-1 tyrosine phosphatase expression correlates with the advanced stages of cutaneous T-cell lymphoma. Hum Pathol, 38, 462-7. https://doi.org/10.1016/j.humpath.2006.09.012
  27. Wlodarski P, Zhang Q, Liu X, et al (2007). PU.1 activates transcription of SHP-1 gene in hematopoietic cells. J Biol Chem, 282, 6316-23.
  28. Xu SB, Liu XH, Li BH, et al (2009). DNA methylation regulates constitutive expression of Stat6 regulatory genes SOCS-1 and SHP-1 in colon cancer cells. J Cancer Res Clin Oncol, 135, 1791-8. https://doi.org/10.1007/s00432-009-0627-z
  29. Xu Z, Gale RP, Zhang Y, et al (2012). Unique features of primary myelofibrosis in Chinese. Blood, 119, 2469-73. https://doi.org/10.1182/blood-2011-11-389866
  30. Zhang J, Somani AK, Siminovitch KA (2000). Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling. Semin Immunol, 12, 361-78. https://doi.org/10.1006/smim.2000.0223
  31. Zhang Q, Wang HY, Marzec M, et al (2005). STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci USA, 102, 6948-53. https://doi.org/10.1073/pnas.0501959102
  32. Zhang Y, Zhao D, Zhao H, et al (2012). Hypermethylation of SHP-1 promoter in patient with high-risk myelodysplastic syndrome and it predicts poor prognosis. Med Oncol, 29, 2359-63. https://doi.org/10.1007/s12032-012-0163-6

Cited by

  1. Acquired JAK-2 V617F Mutational Analysis in Pakistani Patients with Essential Thrombocythemia vol.16, pp.16, 2015, https://doi.org/10.7314/APJCP.2015.16.16.7327
  2. Clinico-Hematological Profile and Risk Stratification in Patients with Essential Thrombocythemia: Experience from Pakistan vol.16, pp.17, 2015, https://doi.org/10.7314/APJCP.2015.16.17.7659
  3. JAK-2 V617F Mutational Analysis in Primary Idiopathic Myelofibrosis: Experience from Southern Pakistan vol.16, pp.17, 2015, https://doi.org/10.7314/APJCP.2015.16.17.7889
  4. Primary Idiopathic Myelofibrosis: Clinico-Epidemiological Profile and Risk Stratification in Pakistani Patients vol.16, pp.18, 2016, https://doi.org/10.7314/APJCP.2015.16.18.8629
  5. Somatic JAK-2 V617F Mutational Analysis in Polycythemia Rubra Vera: a Tertiary Care Center Experience vol.17, pp.3, 2016, https://doi.org/10.7314/APJCP.2016.17.3.1053
  6. Clinico-Epidemiological Profile of Patients with Polycythaemia Rubra Vera - a Five Year Experience from a Tertiary Care Center vol.17, pp.3, 2016, https://doi.org/10.7314/APJCP.2016.17.3.1531
  7. Decitabine combined with all-trans retinoic acid as treatment in a case of primary myelofibrosis transforming into acute myeloid leukaemia vol.47, pp.2, 2019, https://doi.org/10.1177/0300060518820147