Study of SFRP1 and SFRP2 Genes Methylation Status in Patients with De Novo Acute Myeloblastic Leukemia

Document Type : Original Article (s)

Authors

1 MSc Student, Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran

2 Hematology-Oncology and Stem cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Background: Acute myeloid leukemia (AML) is a heterogeneous group of hematologic malignancies with great variability in the pathogenesis and clinical course. DNA methylation of CpG islands within the promoters of specific genes may play roles in tumor initiation and progression. Secreted frizzled-related proteins (SFRPs) are negative regulator of the Wnt signaling pathway. In the present study, we compared the methylation status of SFRP1 and SFRP2 genes promoter in patients with AML and healthy individuals.Methods: In peripheral blood from 43 patients afflicted with de novo AML and 25 healthy controls, isolated DNA was treated with sodium bisulfite and analyzed by methylation-specific polymerase chain reaction (MSP) with primers specific for methylated and unmethylated promoter sequences of the SFRP1 and SFRP2 genes. We used Mann-Whitney u-tests to investigate the correlation between SFRP1 and SFRP2 genes hypermethylation and clinical parameters.Findings: The frequency of aberrant hypermethylation of SFRP1 and SFRP2 genes promoter in patients with AML was determined 30.2% (13/43) and 20.9% (9/43), respectively. In addition, for all subjects in control group, methylation of SFRP1 and SFRP2 genes promoter were negative. Patients with M0 subtype of FAB-AML had the highest incidence of hypermethylation of SFRP1 (P = 0.028) and SFRP2 (P = 0.004) genes promoter.Conclusion: The present study showed that, like many solid tumors, SFRPs genes methylation also occurs in AML. Therefore, the methylation of these genes may play a role in leukemogenesis initiation.

Keywords


  1. Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med 1999; 341(14): 1051-62.
  2. Parkin D, Whelan S, Ferlay J, Teppo L, Thomas D. Cancer incidence in five continents. Vol 3. Lyon, France: IARC Scientific Publications; 2002. p. 155.
  3. Jost E, Schmid J, Wilop S, Schubert C, Suzuki H, Herman JG, et al. Epigenetic inactivation of secreted Frizzled-related proteins in acute myeloid leukaemia. Br J Haematol 2008; 142(5): 745-53.
  4. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008; 8(5): 387-98.
  5. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351(7): 657-67.
  6. Paul S, Dey A. Wnt signaling and cancer development: therapeutic implication. Neoplasma 2008; 55(3): 165-76.
  7. Jones SE, Jomary C. Secreted Frizzled-related proteins: searching for relationships and patterns. Bioessays 2002; 24(9): 811-20.
  8. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20: 781-810.
  9. Marsit CJ, Karagas MR, Andrew A, Liu M, Danaee H, Schned AR, et al. Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res 2005; 65(16): 7081-5.
  10. Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J. Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. J Cell Sci 2008; 121(Pt 6): 737-46.
  11. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16(3): 1215.
  12. Huang ZH, Li LH, Yang F, Wang JF. Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions. World J Gastroenterol 2007; 13(6): 950-4.
  13. Zou H, Molina JR, Harrington JJ, Osborn NK, Klatt KK, Romero Y, et al. Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett's esophagus. Int J Cancer 2005; 116(4): 584-91.
  14. Huang J, Zhang YL, Teng XM, Lin Y, Zheng DL, Yang PY, et al. Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinoma. BMC Cancer 2007; 7: 126.
  15. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 2001; 1(1): 55-67.
  16. Mikesch JH, Steffen B, Berdel WE, Serve H, Muller-Tidow C. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia 2007; 21(8): 1638-47.
  17. Wang H, Fan R, Wang XQ, Wu DP, Lin GW, Xu Y, et al. Methylation of Wnt antagonist genes: a useful prognostic marker for myelodysplastic syndrome. Ann Hematol 2013; 92(2): 199-209.
  18. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429(6990): 457-63.
  19. Nakamoto D, Yamamoto N, Takagi R, Katakura A, Mizoe JE, Shibahara T. Detection of microsatellite alterations in plasma DNA of malignant mucosal melanoma using whole genome amplification. Bull Tokyo Dent Coll 2008; 49(2): 77-87.
  20. Veeck J, Bektas N, Hartmann A, Kristiansen G, Heindrichs U, Knuchel R, et al. Wnt signalling in human breast cancer: expression of the putative Wnt inhibitor Dickkopf-3 (DKK3) is frequently suppressed by promoter hypermethylation in mammary tumours. Breast Cancer Res 2008; 10(5): R82.
  21. Veeck J, Geisler C, Noetzel E, Alkaya S, Hartmann A, Knuchel R, et al. Epigenetic inactivation of the secreted frizzled-related protein-5 (SFRP5) gene in human breast cancer is associated with unfavorable prognosis. Carcinogenesis 2008; 29(5): 991-8.
  22. Cooper SJ, von Roemeling CA, Kang KH, Marlow LA, Grebe SK, Menefee ME, et al. Reexpression of tumor suppressor, sFRP1, leads to antitumor synergy of combined HDAC and methyltransferase inhibitors in chemoresistant cancers. Mol Cancer Ther 2012; 11(10): 2105-15.
  23. Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van EM, Weijenberg MP, et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 2002; 31(2): 141-9.
  24. Fukui T, Kondo M, Ito G, Maeda O, Sato N, Yoshioka H, et al. Transcriptional silencing of secreted frizzled related protein 1 (SFRP 1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene 2005; 24(41): 6323-7.
  25. Qi J, Zhu YQ, Luo J, Tao WH. Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World J Gastroenterol 2006; 12(44): 7113-7.
  26. Muller HM, Oberwalder M, Fiegl H, Morandell M, Goebel G, Zitt M, et al. Methylation changes in faecal DNA: a marker for colorectal cancer screening? Lancet 2004; 363(9417): 1283-5.
  27. Pehlivan M, Sercan Z, Sercan HO. sFRP1 promoter methylation is associated with persistent Philadelphia chromosome in chronic myeloid leukemia. Leuk Res 2009; 33(8): 1062-7.
  28. Hou HA, Kuo YY, Liu CY, Lee MC, Tang JL, Chen CY, et al. Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia. Br J Cancer 2011; 105(12): 1927-33.
  29. Smith M, Barnett M, Bassan R, Gatta G, Tondini C, Kern W. Adult acute myeloid leukaemia. Crit Rev Oncol Hematol 2004; 50(3): 197-222.