• Mohammed Hassan Tahir Department of Biology, University of Sulaimani, Kurdistan Region, Iraq.
  • Dlnya Assad Mohamad Department of Biology, University of Sulaimani, Kurdistan Region, Iraq.
  • Mohammad Hamid Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.




Chronic myeloid leukemia, Wnt signaling, SFRP2, DNA methylation


Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder defined by the chromosomal translocation (t) (9;22) encoding for the BCR-ABL fusion gene. Tumor development and progression may be affected by hypermethylation of promoter regions of certain genes. Secreted Frizzled-Related Proteins (SFRPs) genes produce Wnt signaling antagonists, and their epigenetic silencing has been detected in multiple types of leukaemia. While epigenetic silencing has been broadly reported for SFRPs, SFRP2 is a family member less studied in leukaemia.

To evaluate SFRP2 gene methylation patterns in CML patients compared with healthy individuals.

Materials and Methods
Sodium bisulfite was applied to the extracted DNA from blood samples of 75 CML patients and 25 healthy subjects who served as the control group. The DNA was then analyzed by methylation-specific high-resolution melting (MS-HRM) using specific primers for the SFRP2 gene in promoter sequence.

Forty-five out of 75 CML patients investigated were shown to have SFRP2 methylation percentages between 50% to 100%, whereas 19 out of 25 healthy subjects had a methylation level of less than 50%.

The current study demonstrated that SFRP2 promoter hypermethylation exists in CML, as in several other solid tumours. Hence, methylation of this gene may play a part in initiating leukemogenesis.


Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Practice & Research Clinical Haematology. 2009;22(3):295-302. DOI: https://doi.org/10.1016/j.beha.2009.07.007

Tanizawa A. Optimal management for pediatric chronic myeloid leukaemia. Paediatrics International: official journal of the Japan Pediatric Society. 2016;58(3):171-9. DOI: https://doi.org/10.1111/ped.12876

Wang X, Chen K, Guo G, Chen J-L. Noncoding RNAs and their functional involvement in the regulation of chronic myeloid leukaemia. Briefings in Functional Genomics. 2015;15(3):239-48. DOI: https://doi.org/10.1093/bfgp/elv059

Kikuchi A, Yamamoto H, Sato A, Matsumoto S. Chapter 2 - New Insights into the Mechanism of Wnt Signaling Pathway Activation. In: Jeon KW, editor. International Review of Cell and Molecular Biology. 291: Academic Press; 2011. p. 21-71. DOI: https://doi.org/10.1016/B978-0-12-386035-4.00002-1

Clevers H, Nusse R. Wnt/β-Catenin Signaling and Disease. Cell. 2012;149(6):1192-205. DOI: https://doi.org/10.1016/j.cell.2012.05.012

Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nature Reviews Cancer. 2008;8(5):387-98. DOI: https://doi.org/10.1038/nrc2389

Surana R, Sikka S, Cai W, Shin EM, Warrier SR, Tan HJG, et al. Secreted frizzled-related proteins: Implications in cancers. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2014;1845(1):53-65. DOI: https://doi.org/10.1016/j.bbcan.2013.11.004

Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. The New England journal of medicine. 2003;349(21):2042-54. DOI: https://doi.org/10.1056/NEJMra023075

Liu T-H, Raval A, Chen S-S, Matkovic JJ, Byrd JC, Plass C. CpG Island Methylation and Expression of the Secreted Frizzled-Related Protein Gene Family in Chronic Lymphocytic Leukemia. Cancer Research. 2006;66(2):653-8. DOI: https://doi.org/10.1158/0008-5472.CAN-05-3712

Baharudin R, Tieng FYF, Lee LH, Ab Mutalib NS. Epigenetics of SFRP1: The Dual Roles in Human Cancers. Cancers. 2020;12(2). DOI: https://doi.org/10.3390/cancers12020445

Chen L, Jiang B, Zhong C, Guo J, Zhang L, Mu T, et al. Chemoprevention of colorectal cancer by black raspberry anthocyanins involved the modulation of gut microbiota and SFRP2 demethylation. Carcinogenesis. 2018;39(3):471-81. DOI: https://doi.org/10.1093/carcin/bgy009

Oberwalder M, Zitt M, Wöntner C, Fiegl H, Goebel G, Zitt M, et al. SFRP2 methylation in fecal DNA—a marker for colorectal polyps. International Journal of Colorectal Disease. 2008;23(1):15-9. DOI: https://doi.org/10.1007/s00384-007-0355-2

Liu S, Chen X, Chen R, Wang J, Zhu G, Jiang J, et al. Diagnostic role of Wnt pathway gene promoter methylation in non-small cell lung cancer. Oncotarget. 2017;8(22):36354-67. DOI: https://doi.org/10.18632/oncotarget.16754

Xiao X, Xiao Y, Wen R, Zhang Y, Li X, Wang H, et al. Promoting roles of the secreted frizzled-related protein 2 as a Wnt agonist in lung cancer cells. Oncol Rep. 2015;34(5):2259-66. DOI: https://doi.org/10.3892/or.2015.4221

Miller SA, Dykes DD, Polesky HF. A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic acids research. 1988;16(3):1215. DOI: https://doi.org/10.1093/nar/16.3.1215

Wojdacz TK, Dobrovic A. Methylation-sensitive high resolution melting (MS-HRM): a new approach for sensitive and high-throughput assessment of methylation. Nucleic acids research. 2007;35(6):e41-e. DOI: https://doi.org/10.1093/nar/gkm013

Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annual review of cell and developmental biology. 2004;20:781-810. DOI: https://doi.org/10.1146/annurev.cellbio.20.010403.113126

Fodde R, Smits R, Clevers H. APC, Signal transduction and genetic instability in colorectal cancer. Nature Reviews Cancer. 2001;1(1):55-67. DOI: https://doi.org/10.1038/35094067

Huang J, Zhang Y-L, Teng X-M, Lin Y, Zheng D-L, Yang P-Y, et al. Down-regulation of SFRP1 as a putative tumour suppressor gene can contribute to human hepatocellular carcinoma. BMC Cancer. 2007;7(1):126. DOI: https://doi.org/10.1186/1471-2407-7-126

Mikesch JH, Steffen B, Berdel WE, Serve H, Müller-Tidow C. The emerging role of Wnt signalling in the pathogenesis of acute myeloid leukaemia. Leukemia. 2007;21(8):1638-47. DOI: https://doi.org/10.1038/sj.leu.2404732

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. The New England journal of medicine. 2004;351(7):657-67. DOI: https://doi.org/10.1056/NEJMoa040258

Basu S, Haase G, Ben-Ze’ev A. Wnt signaling in cancer stem cells and colon cancer metastasis. F1000Research. 2016;5. DOI: https://doi.org/10.12688/f1000research.7579.1

Coluccia AM, Vacca A, Duñach M, Mologni L, Redaelli S, Bustos VH, et al. Bcr-Abl stabilizes beta-catenin in chronic myeloid leukaemia through its tyrosine phosphorylation. The EMBO journal. 2007;26(5):1456-66. DOI: https://doi.org/10.1038/sj.emboj.7601485

Khan NI, Bendall LJ. Role of WNT signalling in normal and malignant hematopoiesis. Histology and histopathology. 2006;21(7):761-74.

Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Human Molecular Genetics. 2007;16(R1):R50-R9. DOI: https://doi.org/10.1093/hmg/ddm018

Kim J, Kim S. In silico Identification of SFRP1 as a Hypermethylated Gene in Colorectal Cancers. Genomics & informatics. 2014;12(4):171-80. DOI: https://doi.org/10.5808/GI.2014.12.4.171

Othman Smail H, Asaad Mohamad D. Molecular Approaches for the Detection of DNA Methylation. Academic Journal of Nawroz University. 2022;11(4):452-63. DOI: https://doi.org/10.25007/ajnu.v11n4a1225

Yu J, Xie Y, Li M, Zhou F, Zhong Z, Liu Y, et al. Association between SFRP promoter hypermethylation and different types of cancer: A systematic review and meta‑analysis. Oncol Lett. 2019;18(4):3481-92. DOI: https://doi.org/10.3892/ol.2019.10709

Bennemann K, Galm O, Wilop S, Schubert C, Brümmendorf TH, Jost E. Epigenetic dysregulation of secreted frizzled-related proteins in myeloproliferative neoplasms complements the JAK2V617F-mutation. Clinical epigenetics. 2012;4(1):12. DOI: https://doi.org/10.1186/1868-7083-4-12

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. International Journal of haematology-oncology and stem cell research. 2015;9(1):15-21.

Reins J, Mossner M, Neumann M, Platzbecker U, Schumann C, Thiel E, et al. Transcriptional down-regulation of the Wnt antagonist SFRP1 in haematopoietic cells of patients with different risk types of MDS. Leukemia Research. 2010;34(12):1610-6. DOI: https://doi.org/10.1016/j.leukres.2010.04.013

Roman-Gomez J, Jimenez-Velasco A, Agirre X, Prosper F, Heiniger A, Torres A. Lack of CpG island methylator phenotype defines a clinical subtype of T-cell acute lymphoblastic leukaemia associated with good prognosis. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2005;23(28):7043-9. DOI: https://doi.org/10.1200/JCO.2005.01.4944

Staal FJ, Famili F, Garcia Perez L, Pike-Overzet K. Aberrant Wnt Signaling in Leukemia. Cancers. 2016;8(9). DOI: https://doi.org/10.3390/cancers8090078

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. British journal of haematology. 2008;142(5):745-53. DOI: https://doi.org/10.1111/j.1365-2141.2008.07242.x

Li Z, Luo J. Research on the epigenetic mechanism of SFRP2 in advanced chronic myeloid leukaemia. Biochemical and Biophysical Research Communications. 2018;501(1):64-72. DOI: https://doi.org/10.1016/j.bbrc.2018.04.149



How to Cite

Tahir M, Mohamad D, Hamid M. EVALUATION OF SECRETED FRIZZLED-RELATED PROTEIN-2 METHYLATION STATUS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA. JSMC [Internet]. 2023 Sep. 21 [cited 2024 Jul. 15];13(3):6. Available from: https://jsmc.univsul.edu.iq/index.php/jsmc/article/view/jsmc-10418

Similar Articles

1-10 of 75

You may also start an advanced similarity search for this article.