Promoter Methylation Status and Expression Levels of RASSF1A Gene in Different Phases of Acute Lymphoblastic Leukemia (ALL)
Background: Although the precise pathogenesis of acute lymphoblastic leukemia (ALL) remains unclear, studying gene-regulating mechanisms during ALL pathogeneses may shed light on the underlying mechanisms driving malignant behavior. There is some evidence showing the promoter hypermethylation and silencing of RASSF1A tumor suppressor gene in ALL cells; however, there is a lack of evidence for whether the gene indeed alters during different phases of ALL or in response to therapy. Thus, the current study aimed to clarify this issue using groups of adult ALL patients who have been scarcely investigated regarding expression levels and promoter methylation status.
Materials and Methods: In this case/control study, the expression levels and methylation status of the gene promoter was evaluated using quantitative real-time PCR and methylation-specific PCR (MSP), respectively in adults with ALL. The study included peripheral blood of patients with newly diagnosed ALL (n=10), complete remission (CR) (n=10), or relapse (n=10), and 10 control samples from healthy individuals.
Results: MSP results revealed an unmethylated status for almost all patients and control samples, except a case with relapsing ALL, which showed a hemimethylated pattern. RASSF1A also showed no difference in terms of gene expression in the patients compared with the control group (p>0.05).
Conclusion: The results revealed an up-regulation of RASSF1A tumor suppressor in adult ALL patients experiencing CR, suggesting this to be a marker of therapy response. However, further investigations using more sensitive methylation detecting tools with larger sample sizes may better clarify the involvement of the promoter methylation of RASSF1A in these patients.
2. Yaniv I, Betzer H, Naumov I, et al. Hypermethylation and Expression of Rassf1a in Childhood Acute Lymphoblastic Leukemia (ALL). Blood. 2007;110(11):4141.
3. Azad M, Biniaz RB, Goudarzi M, et al. Short view of leukemia diagnosis and treatment in Iran. Int J Hematol Oncol Stem Cell Res. 2015; 9(2): 88–94.
4. Wong IH, Chan J, Wong J, et al. Ubiquitous aberrant RASSF1A promoter methylation in childhood Neoplasia1. Clin Cancer Res. 2004;10(3):994-1002.
5. Rodak BF, Fritsma GA, Doig K. Hematology clinical principles and applications, 3rd edn. Elsevier Health Sciences: Philadelphia, 2007.
6. Naderi M, Reykande SE, Tabibian S, et al. Childhood acute lymphoblastic leukemia: refusal and abandonmentof treatment in the southeast of Iran. Turk J Med Sci. 2016; 46(3):706-11.
7. Hoffbrand AV (ed). Postgraduate haematology, 7th edn. John Wiley & Sons: United States, 2016.
8. Einav Nili G-Y, Saito Y, Egger G, et al. Cancer epigenetics: modifications, screening, and therapy. Annu Rev Med. 2008;59:267-80.
9. Gallegos-Arreola M, Borjas-Gutiérrez C, Zúñiga-González G, et al. Pathophysiology of Acute Lymphoblastic Leukemia. In: Mejía-Aranguré, JM (ed). Clinical Epidemiology of Acute Lymphoblastic Leukemia-From the Molecules to the Clinic. InTech: Mexico, 2013, pp 43-73.
10. Florean C, Schnekenburger M, Grandjenette C, et al. Epigenomics of leukemia: from mechanisms to therapeutic applications. Epigenomics. 2011;3(5):581-609.
11. Raza M. DNA methylation and cancer ; A Review. Int J Med Papers. 2016; 1: 6–8.
12. Azad M, Kaviani S, Noruzinia M, et al. Gene expression status and methylation pattern in promoter of P15INK4b and P16INK4a in cord blood CD34+ stem cells. Iran J Basic Med Sci. 2013; 16(7): 822–828.
13. Figueroa ME, Reimers M, Thompson RF, et al. An integrative genomic and epigenomic approach for the study of transcriptional regulation. PLoS One. 2008;3(3):e1882.
14. Derakhshanfar E, Alizadeh S, Rafiemehr H, et al. Determination of SFRP1 and SFRP2 Genes Promoter Methylation Status in Patients with Chronic Myelogenous Leukemia. Payavard Salamat. 2017;10(6):514-22.
15. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6):415-28.
16. Bootwala Y, Bandyopadhyay D. Epigenetic therapies of cancer. Curr Canc Ther Rev. 2006;2(2):127-35.
17. van der Weyden L, Adams DJ. The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta. 2007; 1776(1):58-85.
18. Avramouli A, Tsochas S, Mandala E, et al. Methylation status of RASSF1A in patients with chronic myeloid leukemia. Leuk Res . 2009;33(8):1130-2.
19. Hesson LB, Dunwell TL, Cooper WN, et al. The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias. Mol Cancer . 2009;8:42.
20. Wang V, Davis DA, Haque M, et al. Differential gene up-regulation by hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in HEK293T cells. Cancer Res. 2005;65(8):3299-306.
21. Harada K, Toyooka S, Maitra A, et al. Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene. 2002;21(27):4345-9.
22. Hill VK, Dunwell TL, Catchpoole D, et al. Frequent epigenetic inactivation of KIBRA, an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network, is associated with specific genetic event in B-cell acute lymphocytic leukemia. Epigenetics. 2011;6(3):326-32.
23. Danielsen SA, Lind GE, Kolberg M, et al. Methylated RASSF1A in malignant peripheral nerve sheath tumors identifies neurofibromatosis type 1 patients with inferior prognosis. Neuro Oncol. 2015;17(1):63-9.
24. Colombara DV, Eidsmoe D, Stern JE, et al. No Association between p53 Immunohistochemical Staining and RASSF1 or DAPK1 Hypermethylation in Non-Small Cell Lung Cancer. J Cancer Res Ther. 2015; 6(8):631-637.
25. Shinawi T, Hill V, Dagklis A, et al. KIBRA gene methylation is associated with unfavorable biological prognostic parameters in chronic lymphocytic leukemia. Epigenetics. 2012;7(3):211-5.
26. van der Weyden L, Papaspyropoulos A, Poulogiannis G, et al. Loss of RASSF1A synergizes with deregulated RUNX2 signaling in tumorigenesis. Cancer Res. 2012;72(15):3817-27.
27. San Jose-Eneriz E, Agirre X, Rodríguez-Otero P, et al. Epigenetic regulation of cell signaling pathways in acute lymphoblastic leukemia. Epigenomics. 2013;5(5):525-38.
|Issue||Vol 15 No 1 (2021)|
|Expression level; Methylation pattern; RASSF1A gene; Acute lymphoblastic leukemia (ALL)|
|Rights and permissions|
|This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.|