Methylation Status of SOCS1 and SOCS3 Genes in Patients with Acute Lymphoid Leukemia
-
Mahsima Shabani
,
Hanieh Mojtahedi
,
Maryam Sadr
,
Arezou Rezaei
,
Parivash Afradiasbagharani
,
Golshid Sanati
,
Zahra Aryan
,
Farzad Kompani
,
Nima Rezaei
Abstract
Background: Acute Lymphoid Leukemia (ALL) is the leading childhood cancer with a high mortality and
morbidity. Studies have suggested an association of epigenetic transformations with prognosis, recurrence
and immunophenotypes of ALL. SOCS1 and SOCS3 are tumor suppressors inhibiting JAK/STAT signaling
pathway and the resultant aberrant cell proliferation.
Method: We aimed to assess the association between methylation status and ALL, using bone marrow and
peripheral blood samples. 18 patients with ALL and 13 children with no malignancies were included. Using
Bisulfite conversion, quantitative multiplex methylation-specific PCR and 2 -∆∆Ct formula, the methylated
DNA in the promoters of SOCS1 and SOCS3 were measured.
Results: ALL patients had higher mean methylation in SOCS1 promoter and lower mean methylation in
SOCS3 promoter, compared to the control group. However, neither of these mean differences were statistically
significant.
Conclusion: This finding can set the foundation for further large-sample studies with the use of healthy
children as a control group to strengthen the hypothetical association of the methylation status of SOCS1
and SOCS3 with ALL.
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2. Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020 Nov 1;105(11):2524-39
3. Nordlund J, Syvänen A-C, editors. Epigenetics in pediatric acute lymphoblastic leukemia. Semin Cancer Biol; 2018: Elsevier.
4. Lee ST, Muench MO, Fomin ME, Xiao J, Zhou M, de Smith A, et al. Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures. Nucleic Acids Res. 2015;43(5):2590-602.
5. Raboso-Gallego J, Casado-Garcia A, Isidro-Hernandez M, Vicente-Duenas C. Epigenetic Priming in Childhood Acute Lymphoblastic Leukemia. Front Cell Dev Biol. 2019;7:137.
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7. Borssen M, Nordlund J, Haider Z, Landfors M, Larsson P, Kanerva J, et al. DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia. Clin Epigenetics. 2018;10(1):31.
8. Hale V, Hale GA, Brown PA, Amankwah EK. A Review of DNA Methylation and microRNA Expression in Recurrent Pediatric Acute Leukemia. Oncology. 2017;92(2):61-67.
9. Borssén M. DNA methylation as a prognostic marker in acute lymphoblastic leukemia.2016.
10. Jimenez-Morales S, Hidalgo-Miranda A, Ramirez-Bello J. [Acute lymphoblastic leukemia: a genomic perspective]. Bol Med Hosp Infant Mex. 2017;74(1):13-26.
11. Chaudhari S, Desai JS, Adam A, Mishra P. JAK/STAT as a novel target for treatment of leukemia. Int J Pharm Pharm Sci. 2014;6(1):1-7.
12. Zhang J, Li H, Yu JP, Wang SE, Ren XB. Role of SOCS1 in tumor progression and therapeutic application. Int J Cancer. 2012;130(9):1971-80.
13. Sasi W, Sharma AK, Mokbel K. The role of suppressors of cytokine signalling in human neoplasms. Mol Biol Int. 2014;2014:630797.
14. Kim MH, Kim MS, Kim W, Kang MA, Cacalano NA, Kang SB, et al. Suppressor of cytokine signaling (SOCS) genes are silenced by DNA hypermethylation and histone deacetylation and regulate response to radiotherapy in cervical cancer cells. PLoS One. 2015;10(4):e0123133.
15. Chen SS, Wu WZ, Zhang YP, Huang WJ. Gene polymorphisms of SOCS1 and SOCS2 and acute lymphoblastic leukemia. Eur Rev Med Pharmacol Sci. 2020;24(10):5564-72.
16. Wahlberg P, Lundmark A, Nordlund J, Busche S, Raine A, Tandre K, et al. DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands. Epigenomics. 2016;8(10):1367-87.
17. Baylin SB, Jones PA. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016;8(9):a019505.
18. Florea ID, Karaoulani C. Epigenetic Changes of the Immune System with Role in Tumor Development. Methods Mol Biol. 2018;1856:203-18.
19. Chen CY, Tsay W, Tang JL, Shen HL, Lin SW, Huang SY, et al. SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia. Genes Chromosomes Cancer. 2003;37(3):300-5.
20. Sasi W, Jiang WG, Sharma A, Mokbel K. Higher expression levels of SOCS 1,3,4,7 are associated with earlier tumour stage and better clinical outcome in human breast cancer. BMC Cancer. 2010;10(1):178.
21. Inagaki-Ohara K, Kondo T, Ito M, Yoshimura A. SOCS, inflammation, and cancer. JAKSTAT. 2013;2(3):e24053.
22. Zhang Q, Shi C, Han L, Jain N, Roberts KG, Ma H, et al. Inhibition of mTORC1/C2 signaling improves anti-leukemia efficacy of JAK/STAT blockade in CRLF2 rearranged and/or JAK driven Philadelphia chromosome-like acute B-cell lymphoblastic leukemia. Oncotarget. 2018;9(8):8027-41.
23. Song S, Wang Y, Wang J, Lian W, Liu S, Zhang Z, et al. Tumour-derived IL-10 within tumour microenvironment represses the antitumour immunity of Socs1-silenced and sustained antigen expressing DCs. Eur J Cancer. 2012;48(14):2252-59.
24. Tang Y, Kitisin K, Jogunoori W, Li C, Deng C-X, Mueller SC, et al. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling. P NATL A SCI INDIA A. 2008;105(7):2445-50.
25. Mah WC, Lee CG. DNA methylation: potential biomarker in Hepatocellular Carcinoma. Biomark Res. 2014;2(1):5.
26. Zhang XH, Yang L, Liu XJ, Zhan Y, Pan YX, Wang XZ, et al. Association between methylation of tumor suppressor gene SOCS1 and acute myeloid leukemia. Oncol Rep. 2018;40(2):1008-16.
27. Meyer LK, Hermiston ML. The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities. Cancer Drug Resist. 2019;2(2):313-25.
28. Huang L, Hu B, Ni J, Wu J, Jiang W, Chen C, et al. Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis. J Exp Clin Cancer Res. 2016;35:27.
29. Brender C, Lovato P, Sommer VH, Woetmann A, Mathiesen AM, Geisler C, et al. Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha. Leukemia 2005;19(2):209-13.
30. Fojtova M, Boudny V, Kovarik A, Lauerova L, Adamkova L, Souckova K, et al. Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells. Br J Cancer. 2007;97(2):231-37.
31. Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene. 2013;32(21):2601-13.
32. Pierconti F, Martini M, Pinto F, Cenci T, Capodimonti S, Calarco A, et al. Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior. Prostate. 2011;71(3):318-25.
33. Martini M, Pallini R, Luongo G, Cenci T, Lucantoni C, Larocca LM. Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme. Int J Cancer. 2008;123(12):2955-60.
34. Liu K, Wu Z, Chu J, Yang L, Wang N. Promoter methylation and expression of SOCS3 affect the clinical outcome of pediatric acute lymphoblastic leukemia by JAK/STAT pathway. Biomed Pharmacother. 2019;115:108913.
2. Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020 Nov 1;105(11):2524-39
3. Nordlund J, Syvänen A-C, editors. Epigenetics in pediatric acute lymphoblastic leukemia. Semin Cancer Biol; 2018: Elsevier.
4. Lee ST, Muench MO, Fomin ME, Xiao J, Zhou M, de Smith A, et al. Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures. Nucleic Acids Res. 2015;43(5):2590-602.
5. Raboso-Gallego J, Casado-Garcia A, Isidro-Hernandez M, Vicente-Duenas C. Epigenetic Priming in Childhood Acute Lymphoblastic Leukemia. Front Cell Dev Biol. 2019;7:137.
6. Ramos KN, Ramos IN, Zeng Y, Ramos KS. Genetics and epigenetics of pediatric leukemia in the era of precision medicine. F1000Res. 2018;7.
7. Borssen M, Nordlund J, Haider Z, Landfors M, Larsson P, Kanerva J, et al. DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia. Clin Epigenetics. 2018;10(1):31.
8. Hale V, Hale GA, Brown PA, Amankwah EK. A Review of DNA Methylation and microRNA Expression in Recurrent Pediatric Acute Leukemia. Oncology. 2017;92(2):61-67.
9. Borssén M. DNA methylation as a prognostic marker in acute lymphoblastic leukemia.2016.
10. Jimenez-Morales S, Hidalgo-Miranda A, Ramirez-Bello J. [Acute lymphoblastic leukemia: a genomic perspective]. Bol Med Hosp Infant Mex. 2017;74(1):13-26.
11. Chaudhari S, Desai JS, Adam A, Mishra P. JAK/STAT as a novel target for treatment of leukemia. Int J Pharm Pharm Sci. 2014;6(1):1-7.
12. Zhang J, Li H, Yu JP, Wang SE, Ren XB. Role of SOCS1 in tumor progression and therapeutic application. Int J Cancer. 2012;130(9):1971-80.
13. Sasi W, Sharma AK, Mokbel K. The role of suppressors of cytokine signalling in human neoplasms. Mol Biol Int. 2014;2014:630797.
14. Kim MH, Kim MS, Kim W, Kang MA, Cacalano NA, Kang SB, et al. Suppressor of cytokine signaling (SOCS) genes are silenced by DNA hypermethylation and histone deacetylation and regulate response to radiotherapy in cervical cancer cells. PLoS One. 2015;10(4):e0123133.
15. Chen SS, Wu WZ, Zhang YP, Huang WJ. Gene polymorphisms of SOCS1 and SOCS2 and acute lymphoblastic leukemia. Eur Rev Med Pharmacol Sci. 2020;24(10):5564-72.
16. Wahlberg P, Lundmark A, Nordlund J, Busche S, Raine A, Tandre K, et al. DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands. Epigenomics. 2016;8(10):1367-87.
17. Baylin SB, Jones PA. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016;8(9):a019505.
18. Florea ID, Karaoulani C. Epigenetic Changes of the Immune System with Role in Tumor Development. Methods Mol Biol. 2018;1856:203-18.
19. Chen CY, Tsay W, Tang JL, Shen HL, Lin SW, Huang SY, et al. SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia. Genes Chromosomes Cancer. 2003;37(3):300-5.
20. Sasi W, Jiang WG, Sharma A, Mokbel K. Higher expression levels of SOCS 1,3,4,7 are associated with earlier tumour stage and better clinical outcome in human breast cancer. BMC Cancer. 2010;10(1):178.
21. Inagaki-Ohara K, Kondo T, Ito M, Yoshimura A. SOCS, inflammation, and cancer. JAKSTAT. 2013;2(3):e24053.
22. Zhang Q, Shi C, Han L, Jain N, Roberts KG, Ma H, et al. Inhibition of mTORC1/C2 signaling improves anti-leukemia efficacy of JAK/STAT blockade in CRLF2 rearranged and/or JAK driven Philadelphia chromosome-like acute B-cell lymphoblastic leukemia. Oncotarget. 2018;9(8):8027-41.
23. Song S, Wang Y, Wang J, Lian W, Liu S, Zhang Z, et al. Tumour-derived IL-10 within tumour microenvironment represses the antitumour immunity of Socs1-silenced and sustained antigen expressing DCs. Eur J Cancer. 2012;48(14):2252-59.
24. Tang Y, Kitisin K, Jogunoori W, Li C, Deng C-X, Mueller SC, et al. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling. P NATL A SCI INDIA A. 2008;105(7):2445-50.
25. Mah WC, Lee CG. DNA methylation: potential biomarker in Hepatocellular Carcinoma. Biomark Res. 2014;2(1):5.
26. Zhang XH, Yang L, Liu XJ, Zhan Y, Pan YX, Wang XZ, et al. Association between methylation of tumor suppressor gene SOCS1 and acute myeloid leukemia. Oncol Rep. 2018;40(2):1008-16.
27. Meyer LK, Hermiston ML. The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities. Cancer Drug Resist. 2019;2(2):313-25.
28. Huang L, Hu B, Ni J, Wu J, Jiang W, Chen C, et al. Transcriptional repression of SOCS3 mediated by IL-6/STAT3 signaling via DNMT1 promotes pancreatic cancer growth and metastasis. J Exp Clin Cancer Res. 2016;35:27.
29. Brender C, Lovato P, Sommer VH, Woetmann A, Mathiesen AM, Geisler C, et al. Constitutive SOCS-3 expression protects T-cell lymphoma against growth inhibition by IFNalpha. Leukemia 2005;19(2):209-13.
30. Fojtova M, Boudny V, Kovarik A, Lauerova L, Adamkova L, Souckova K, et al. Development of IFN-γ resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells. Br J Cancer. 2007;97(2):231-37.
31. Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene. 2013;32(21):2601-13.
32. Pierconti F, Martini M, Pinto F, Cenci T, Capodimonti S, Calarco A, et al. Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior. Prostate. 2011;71(3):318-25.
33. Martini M, Pallini R, Luongo G, Cenci T, Lucantoni C, Larocca LM. Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme. Int J Cancer. 2008;123(12):2955-60.
34. Liu K, Wu Z, Chu J, Yang L, Wang N. Promoter methylation and expression of SOCS3 affect the clinical outcome of pediatric acute lymphoblastic leukemia by JAK/STAT pathway. Biomed Pharmacother. 2019;115:108913.
| Files | ||
| Issue | Vol 5, No 2 (2022) | |
| Section | Review Article | |
| DOI | https://doi.org/10.18502/igj.v5i2.15097 | |
| Keywords | ||
| ALL Epigenetic Leukemia Methylation SOCS | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Shabani M, Mojtahedi H, Sadr M, Rezaei A, Afradiasbagharani P, Sanati G, Aryan Z, Kompani F, Rezaei N. Methylation Status of SOCS1 and SOCS3 Genes in Patients with Acute Lymphoid Leukemia. Immunol Genet J. 2022;5(2):69-76.
