Study of SFRP1 and SFRP2 methylation status in patients with de novo Acute Myeloblastic Leukemia

  • Ali Ghasemi MSc, Department of Hematology, School of Allied Medical Sciences, Tehran university of Medical Sciences, Tehran, Iran.
  • Shahrbano Rostami PhD, Assistant Professor, Hematology-Oncology and Stem cell Transplantation Research Center, Tehran university of Medical Sciences, Tehran, Iran.
  • Bahram Chahardouli PhD, Assistant Professor, Hematology-Oncology and Stem cell Transplantation Research Center, Tehran university of Medical Sciences, Tehran, Iran.
  • Nasrin Alizad Ghandforosh MSc, Hematology-Oncology and Stem cell Transplantation Research Center, Tehran university of Medical Sciences, Tehran, Iran.
  • Abbas Ghotaslou MSc, Department of Hematology, School of Allied Medical Sciences, Tehran university of Medical Sciences, Tehran, Iran.
  • Fatemeh Nadali Mail PhD, Associate Professor, Department of Hematology, School of Allied Medical Sciences, Tehran university of Medical Sciences, Tehran, Iran.
Keywords:
AML, DNA Methylation, SFRP

Abstract

Intoduction: Acute myeloid leukemia (AML) is a heterogeneous group of hematologic malignancies with abundant changeability in the pathogenesis. 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 examined the methylation status of SFRP1 and SFRP2 genes in patients with AML.
Methods:
Isolated DNA from peripheral blood of 43 AML patients and 25 healthy subjects as a control group was treated with sodium bisulfite 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 & -2 genes. We used Mann-Whitney u-tests to investigate the correlation between SFRP1 and SFRP2 genes hypermethylation and clinical parameters.
Results:
The frequency of aberrant hypermethylation of SFRP1 and SFRP2 genes 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 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).
Conclusion: The present study showed that, like many solid tumors, methylation of SFRP genes also occurs in AML. Therefore, the methylation of these genes may play a role in the initiation of leukmogenesis.

References

Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. New England Journal of Medicine. 1999;341(14):1051-62.

Parkin D, Whelan S, Ferlay J, et al. Cancer incidence in five continents Vol. VIII. IARC scientific publications. 2002;155.

Jost E, Schmid J, Wilop S, et al. Epigenetic inactivation of secreted Frizzled‐related proteins in acute myeloid leukaemia. British journal of haematology. 2008;142(5):745-53.

Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nature Reviews Cancer. 2008;8(5):387-98.

Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. New England Journal of Medicine. 2004;351(7):657-67.

Paul S, Dey A. Wnt signaling and cancer development: therapeutic implication. Neoplasma. 2007;55(3):165-76.

Jones SE, Jomary C. Secreted Frizzled‐related proteins: searching for relationships and patterns. Bioessays. 2002;24(9):811-20.

Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781-810.

Marsit CJ, Karagas MR, Andrew A, et al. Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer research. 2005;65(16):7081-5.

Bovolenta P, Esteve P, Ruiz JM, et al. Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. Journal of cell science. 2008;121(6):737-46.

Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic acids research. 1988;16(3):1215.

Huang Z-H, Li L-H, Yang F,et al. Detection of aberrant methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions. World Journal of Gastroenterology. 2007;13(6):950.

Zou H, Molina JR, Harrington JJ, et al. Aberrant methylation of secreted frizzled‐related protein genes in esophageal adenocarcinoma and Barrett's esophagus. International Journal of Cancer. 2005;116(4):584-91.

Huang J, Zhang Y-L, Teng X-M, et al. Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinoma. BMC cancer. 2007;7(1):126.

Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nature Reviews Cancer. 2001;1(1):55-67.

Mikesch J, Steffen B, Berdel W, et al. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia. 2007;21(8):1638-47.

Wang H, Fan R, Wang X-Q, et al. Methylation of Wnt antagonist genes: a useful prognostic marker for myelodysplastic syndrome. Annals of hematology. 2013;92(2):199-209.

Egger G, Liang G, Aparicio A, et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457-63.

Nakamoto D, Yamamoto N, Takagi R, et al. Detection of microsatellite alterations in plasma DNA of malignant mucosal melanoma using whole genome amplification. The Bulletin of Tokyo Dental College. 2008;49(2):77-87.

Veeck J, Bektas N, Hartmann A, 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.

Veeck J, Geisler C, Noetzel E,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.

Cooper SJ, Von Roemeling CA, Kang KH, et al. Reexpression of tumor suppressor, sFRP1, leads to antitumor synergy of combined HDAC and methyltransferase inhibitors in chemoresistant cancers. Molecular Cancer Therapeutics. 2012;11(10):2105-15.

Suzuki H, Gabrielson E, Chen W, et al. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nature genetics. 2002;31(2):141-9.

Fukui T, Kondo M, Ito G, et al. Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene. 2005;24(41):6323-7.

Qi J, Zhu Y-Q, Luo J, et al. Hypermethylation and expression regulation of secreted frizzled-related protein genes in colorectal tumor. World Journal of Gastroenterology. 2006;12(44):7113.

Müller HM, Oberwalder M, Fiegl H, et al. Methylation changes in faecal DNA: a marker for colorectal cancer screening? The Lancet. 2004;363(9417):1283-5.

Valencia A, Roman-Gomez J, Cervera J, et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia. 2009;23(9):1658-66.

Hou H, Kuo Y, Liu C, et al. Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia. British journal of cancer. 2011;105(12):1927-33.

.Pehlivan M, Sercan Z, Sercan HO. sFRP1 promoter methylation is associated with persistent Philadelphia chromosome in chronic myeloid leukemia. Leukemia Research. 2009;33(8):1062-7.

Griffiths EA, Gore SD, Hooker C, et al. Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation. Leukemia & lymphoma. 2010;51(9):1711-9.

Cheng CK, Li L, Cheng SH, et al. Secreted-frizzled related protein 1 is a transcriptional repression target of the t (8; 21) fusion protein in acute myeloid leukemia. Blood. 2011;118(25):6638-48.

How to Cite
1.
Ghasemi A, Rostami S, Chahardouli B, Alizad Ghandforosh N, Ghotaslou A, Nadali F. Study of SFRP1 and SFRP2 methylation status in patients with de novo Acute Myeloblastic Leukemia. Int J Hematol Oncol Stem Cell Res. 9(1):15-21.
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