Polymorphism of Interleukins and Tumor Necrosis Factor α Genes in Multiple Myeloma Patients with Autologous Hematopoietic Stem Cell Transplantation

Aim. To assess polymorphism value of interleukins (IL6, IL1B, IL10) and tumor necrosis factor α (TNF) genes in multiple myeloma (MM) patients who received autologous hematopoietic stem cell transplantation (auto-HSCT).

Materials & Methods. The study enrolled 37 MM patients (15 men and 22 women) aged 38–66 years (mean age 54.5 ± 6.4 years), who received auto-HSCT. After transplantation, partial (PR), very good partial (VGPR), and complete (CR) responses were reported in 11, 7, and 19 patients, respectively. In 23 (62.2 %) patients CD34+ cell collection on the day of the first leukocytapheresis session exceeded the suboptimal level of 2.5 × 10⁶/kg. The control group included 236 healthy subjects. Genotyping by PCR with subsequent analysis of restriction fragment length polymorphism of amplified products was performed. To identify between-group differences in genotype distribution, Fisher’s exact test with measurements of odds ratio (OR) and р–value was used.

Results. The study group of patients was distinguished from the control group by more than twofold increased proportion of homozygous IL1B –31C (OR 2.7; p = 0.029). The proportion of heterozygous –174G/C allelic variant of IL6 gene in the subgroup of patients with CR after auto-HSCT was considerably higher than in patients with VGPR and PR (OR 5.6; p = 0.022). In the subgroup of patients with CD34+ cell collection > 2.5 × 10⁶/kg the proportion of those with IL10 –592C/C genotype was twice as high as in patients with lower CD34+ cell collection (OR 3.9; p = 0.091).

Conclusion. The present study confirms the relationship of –31C/Т polymorphism in IL1B gene in homozygous state with higher MM risk. It proved the association of –174G/C polymorphism in IL6 gene and –592C/A polymorphism in IL10 gene with the chosen criteria for auto-HSCT efficacy. To precisely clarify the value of variants in the above genes for predicting chemotherapy effect in MM, further studies involving more patients are required.

• Svetlana Pavlovna Svitina Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024
• Zh.Yu. Sidorova Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024
• I.I. Kostroma Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024
• A.A. Zhernyakova Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024
• A.V. Chechetkin Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024
• Zh.V. Chubukina Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024
• S.V. Gritsaev Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024
• S.I. Kapustin Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024
• S.S. Bessmeltsev Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024 ; ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА России», ул. 2-я Советская, д. 16, Санкт-Петербург, Российская Федерация, 191024

1. Бессмельцев С.С. Множественная миелома (патогенез, клиника, диагностика, дифференциальный диагноз). Часть Клиническая онкогематология. 2013;6(3):237–57. DOI: https://doi.org/10.21320/2500-2139-2013-6-3-237-257
2. [Bessmeltsev SS. Multiple myeloma (pathogenesis, clinical features, diagnosis, differential diagnosis). Part I. Klinicheskaya onkogematologiya. 2013;6(3):237–57. (In Russ)]
3. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома: руководство для врачей. М.: СИМК, 2016. 512 с.
4. [Bessmeltsev SS, Abdulkadyrov KM. Mnozhestvennaya mieloma: rukovodstvo dlya vrachei. (Multiple myeloma: manual for physicians.) Moscow: SIMK Publ.; 2016. 512 p. (In Russ)]
5. Грицаев С.В., Кузяева А.А., Бессмельцев С.С. Отдельные аспекты аутологичной трансплантации гемопоэтических стволовых клеток при множественной миеломе. Клиническая онкогематология. 2017;10(1):7–12. doi: 10.21320/2500-2139-2017-10-1-7-12. DOI: https://doi.org/10.21320/2500-2139-2017-10-1-7-12
6. [Gritsaev SV, Kuzyaeva AA, Bessmel’tsev SS. Certain Aspects of Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma. Clinical oncohematology. 2017;10(1):7–12. doi: 10.21320/2500-2139-2017-10-1-7-12. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2017-10-1-7-12
7. Бессмельцев С.С. Множественная миелома (лечение первичных больных): обзор литературы и собственные данные. Часть Клиническая онкогематология. 2013;6(4):379–414. DOI: https://doi.org/10.21320/2500-2139-2013-6-4-379-414
8. [Bessmeltsev SS. Multiple myeloma (management of newly diagnosed patients): literature review and our on data. Part II. Klinicheskaya onkogematologiya. 2013;6(4):379–414. (In Russ)]
9. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома. Современный взгляд на проблему. Алматы: Коста, 2007. 480 c.
10. [Bessmeltsev SS, Abdulkadyrov KM. Mnozhestvennaya mieloma. Sovremennyi vzglyad na problemu. (Multiple myeloma. Current view on the problem.) Almaty: Kosta Publ.; 2007. 480 p. (In Russ)]
11. Назарова Е.Л., Минаева Н.В., Хоробрых М.Н. и др. Прогностическое значение генетических маркеров в оценке эффективности индукционной терапии, включающей аутологичную трансплантацию гемопоэтических стволовых клеток, у больных множественной миеломой. Клиническая онкогематология. 2018;11(1):54–69. doi: 10.21320/2500-2139-2018-11-1-54-69. DOI: https://doi.org/10.21320/2500-2139-2018-11-1-54-69
12. [Nazarova EL, Minaeva NV, Khorobrykh MN, et al. Prognostic Value of Genetic Markers for Efficacy Estimation of Induction Treatment Including Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients. Clinical oncohematology. 2018;11(1):54–69. doi: 10.21320/2500-2139-2018-11-1-54-69. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2018-11-1-54-69
13. Vangsted AJ, Klausen TW, Ruminski W, et al. The polymorphism IL-1β T-31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto-SCT. Bone Marrow Transplant. 2009;43(7):539–45. doi: 10.1038/bmt.2008.351. DOI: https://doi.org/10.1038/bmt.2008.351
14. Kasamatsu T, Saitoh T, Ino R, et al. Polymorphism of IL-10 receptor β affects the prognosis of multiple myeloma patients treated with thalidomide and/or bortezomib. Hematol Oncol. 2017;35(4):711–18. doi: 10.1002/hon.2322. DOI: https://doi.org/10.1002/hon.2322
15. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res. 1988;16(3):1215–8. doi: 10.1093/nar/16.3.1215. DOI: https://doi.org/10.1093/nar/16.3.1215
16. Mullis KB, Faloona FA. Specific synthesis of DNA via a polymerase-catalysed chain reaction. Methods Enzymol. 1987;155:335–50. doi: 10.1016/0076-6879(87)55023-6. DOI: https://doi.org/10.1016/0076-6879(87)55023-6
17. Zheng C, Huang DR, Bergenbrant S, et al. Interleukin 6, tumor necrosis factor alpha, interleukin 1 beta and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma. Br J Haematol. 2000;109(1):39– doi: 10.1046/j.1365-2141.2000.01963.x. DOI: https://doi.org/10.1046/j.1365-2141.2000.01963.x
18. Wang X, Jiang F, Liang Y, et al. Interleukin-1β -31C/T and -511T/C Polymorphisms Were Associated with Preeclampsia in Chinese Han Population. PLoS One. 2014;9(9):1– doi: 10.18632/oncotarget.23472. DOI: https://doi.org/10.1371/journal.pone.0106919
19. Alexander DD, Mink PJ, Adami HO, et al. Multiple myeloma: a review of the epidemiologic literature. Int J Cancer. 2007;120(S12):40–61. doi: 10.1002/ijc.22718. DOI: https://doi.org/10.1002/ijc.22718
20. Павлова А.А., Павлова И.Е., Бубнова Л.Н. и др. Взаимосвязь однонуклеотидного полиморфизма генов цитокинов и клинико-лабораторных показателей у больных множественной миеломой. Медицинская иммунология. 2019;21(4):703–14. doi: 10.15789/1563-0625-2019-4-703-714. DOI: https://doi.org/10.15789/1563-0625-2019-4-703-714
21. [Pavlova AA, Pavlova IE, Bubnova LN, et al. Relationship between single nucleotide polymorphisms in cytokine genes and clinical laboratory parameters in patients with multiple myeloma. Meditsinskaya Immunologiya. 2019;21(4):703–14. doi: 10.15789/1563-0625-2019-4-703-714. (In Russ)] DOI: https://doi.org/10.15789/1563-0625-2019-4-703-714
22. Ghobrial IM. Myeloma as a model for the process of metastasis: implications for therapy. Blood. 2012;120(1):20–30. doi: 10.1182/blood-2012-01-379024. DOI: https://doi.org/10.1182/blood-2012-01-379024
23. Насонов Е.Л. Роль интерлейкина 1 в развитии заболеваний человека. Научно-практическая ревматология. 2018;56:19–27. doi: 10.14412/1995-4484-2018-19-27. DOI: https://doi.org/10.14412/1995-4484-2018-19-27
24. [Nasonov EL. The role of interleukin 1 in the development of human diseases. Nauchno-Prakticheskaya Revmatologiya. 2018;56:19–27. doi: 10.14412/1995-4484-2018-19-27. (In Russ)] DOI: https://doi.org/10.14412/1995-4484-2018-19-27
25. Costes V, Portier M, Lu ZY, et al. Interleukin-1 in multiple myeloma: producer cells and their role in the control of IL-6 production. Br J Haematol. 1998;103(4):1152–60. doi: 10.1046/j.1365-2141.1998.01101.x. DOI: https://doi.org/10.1046/j.1365-2141.1998.01101.x
26. Lacy MQ, Donovan KA, Heimbach JK, et al. Comparison of interleukin-1 beta expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma. Blood. 1999;93(1):300–5. doi: 10.1182/blood.V93.1.300. DOI: https://doi.org/10.1182/blood.V93.1.300
27. Xiong Y, Donovan KA, Kline MP, et al. Identification of two groups of smoldering multiple myeloma patients who are either high or low producers of interleukin-1. J Interferon Cytokine Res. 2006;26(2):83–95. doi: 0.1089/jir.2006.26.83. DOI: https://doi.org/10.1089/jir.2006.26.83
28. Honemann D, Chatterjee M, Savino R, et al. The IL-6 receptor antagonist SANT-7 overcomes bone marrow stromal cell-mediated drug resistance of multiple myeloma cells. Int J Cancer. 2001;93(5):674–80. doi: 10.1002/ijc.1388. DOI: https://doi.org/10.1002/ijc.1388
29. Lauta VM. A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. Cancer. 2003;97(10):2440–52. doi: 10.1002/cncr.11072. DOI: https://doi.org/10.1002/cncr.11072
30. Chakraborty B, Vishnoi G, Gowda SH, Goswami B. Interleukin-6 gene-174 G/C promoter polymorphism and its association with clinical profile of patients with multiple myeloma. Asia Pac J Clin Oncol. 2014;13(5):402–7. doi: 10.1111/ajco.12290. DOI: https://doi.org/10.1111/ajco.12290
31. Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275(24):18138–44. doi: 10.1074/jbc.M000379200. DOI: https://doi.org/10.1074/jbc.M000379200
32. Ray A, Sassone-Corsi P, Sehgal PB. A multiple cytokine- and second messenger-responsive element in the enhancer of the human interleukin-6 gene: similarities with c-fos gene regulation. Mol Cell Biol. 1989;9(12):5537–47. doi: 10.1128/mcb.9.12.5537. DOI: https://doi.org/10.1128/MCB.9.12.5537
33. Duch CR, Figueiredo MS, Ribas C, et al. Analysis of polymorphism at site -174 G/C of interleukin-6 promoter region in multiple myeloma. Braz J Med Biol Res. 2007;40(2):265–7. doi: 10.1590/s0100-879х2007000200014. DOI: https://doi.org/10.1590/S0100-879X2007000200014
34. Mazur G, Bogunia-Kubik K, Wrobel T, et al. IL-6 and IL-10 promoter gene polymorphisms do not associate with the susceptibility for multiple myeloma. Immunol Lett. 2005;96(2):241–6. doi: 10.1016/j.imlet.2004.08.015. DOI: https://doi.org/10.1016/j.imlet.2004.08.015
35. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res. 1988;16(3):1215–8. doi: 10.1093/nar/16.3.1215. DOI: https://doi.org/10.1093/nar/16.3.1215
36. Banu C, Moise A, Arion CV, et al. Cytokine Gene Polymorphisms support diagnostic monitoring of Romanian multiple myeloma patients. J Med Life. 2011;4(3):264–8.
37. Rousset F, Garcia E, Defrance T, et al. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci USA. 1992;89(5):1890–3. doi: 10.1073/pnas.89.5.1890. DOI: https://doi.org/10.1073/pnas.89.5.1890
38. Taga K, Tosato G. IL-10 inhibits human T cell proliferation and IL-2 production. J Immunol. 1992;148(4):1143–8. DOI: https://doi.org/10.4049/jimmunol.148.4.1143
39. Mosser DM, Zhang X. Interleukin-10: new perspectives on an old cytokine. Immunol Rev. 2008;226(1):205–18. doi: 10.1111/j.1600-065X.2008.00706.x. DOI: https://doi.org/10.1111/j.1600-065X.2008.00706.x
40. Kingo K, Ratsep R, Koks S, et al. Influence of genetic polymorphisms on interleukin-10 mRNA expression and psoriasis susceptibility. J Dermatol Sci. 2005;37(2):111–3. doi: 10.1016/j.jdermsci.2004.10.002. DOI: https://doi.org/10.1016/j.jdermsci.2004.10.002
41. Howell MW. Interleukin-10 Gene Polymorphisms and Cancer. Madame Curie Bioscience Database [Internet]. Landes Bioscience; 2000–2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6117/ (accessed 4.03.2021).
42. Sabouri AH, Saito M, Lloyd AL, et al. Polymorphism in the interleukin-10 promoter affects both provirus load and the risk of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis. J Infect Dis. 2004;190(7):1279–85. doi: 10.1086/423942. DOI: https://doi.org/10.1086/423942
43. Zhang X, Hei P, Deng L, Lin J. Interleukin-10 gene promoter polymorphism and their protein production in peritoneal fluid in patients with endometriosis. Mol Hum Reprod. 2007;13(2):135–40. doi: 10.1093/molehr/gal106. DOI: https://doi.org/10.1093/molehr/gal106