EL Nazarova, NV Minaeva, MN Khorobrykh, EE Sukhorukova, VI Shardakov, IV Paramonov, NA Zorina

Kirov Research Institute of Hematology and Blood Transfusion, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027

For correspondence: Elena L’vovna Nazarova, PhD, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027; e-mail: nazarova@niigpk.ru

For citation: 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

---

ABSTRACT

Aim. To determine the value of polymorphisms of the immune response genes for the treatment efficacy in MM patients receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autoHSCT).

Methods. The overall of 20 ММ patients (8 men and 12 women) were included in the study. The median age was 51.5 years (range 32–67). Clinical laboratory tests had been performed before melphalan high-dose (200 mg/m²) conditioning therapy. In accordance with the achieved anticancer response to induction treatment the patients were divided into 3 groups: patients with partial remission (group 1; n = 7); patients with very good partial remission (group 2; n = 9); patients with complete remission (group 3; n = 4). Genotyping of 20 polymorphic loci of 14 immune response genes was performed using PCR.

Results. The study showed that group 2 had no AA mutant homozygotes of IL10 in the G-1082A polymorphic locus compared to group 3 and no TT mutant homozygotes of TLR6 (Ser249Pro) compared to group 1. The patients with more pronounced mucositis (grade 2/3) compared to patients with minor mucositis (grade 0/1) had no CC mutant homozygotes of IL1β in the G-1473C position and a smaller number of (CT+TT) heterozygous and homozygous haplotype carriers of IL10 with the T mutant allele in the C-819T mutation point. The multivariate analysis showed that the genetic marker statistically effecting the progression-free survival rates in MM patients after high-dose chemotherapy and autoHSCT was the polymorphous status of the IL10 (G-1082A), TNF (G-308A), TLR4 (Thr399Ile), and TLR9 in the T-1237C and A2848 polymorphic loci. Progression-free survival rates correlated with the mutation status of IL1β (T-511C), IL2 (T-330G), IL6 (C-174G), CD14 (C-159T), TLR3 (Phe421Leu), and TLR4 (Asp299Gly).

Conclusion. The obtained data show the correlation of 14 polymorphisms of 10 immune response genes with the immediate results of the induction treatment, and also with the severity of mucositis during the early post-transplant period, as well as overall and progression-free survival rates in MM patients. Due to a small sample volume further studies will be planned with the aim to verify the identified trends. The suggested hypothesis for immune response gene polymorphism effecting a disease prognosis can substantially contribute to developing of individualized approach to MM treatment.

Keywords: multiple myeloma, gene polymorphisms, immune response, cytokine, Toll-like receptor, high-dose chemotherapy, autologous hematopoietic stem cell transplantation.

Received: August 18, 2017

Accepted: November 7, 2017

Read in PDF 

---

REFERENCES

1. Martino A, Buda G, Maggini V, et al. Could age modify the effect of genetic variants in IL6 and TNF-α genes in multiple myeloma? Leukemia Res. 2012;36(5):594–7. doi: 10.1016/j.leukres.2012.02.009.
2. Ludwig H, Durie BGM, Bolejack V, et al. Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group. Blood. 2008;111(8):4039–47. doi: 10.1182/blood-2007-03-081018.
3. Harsini S, Beigy M, Akhavan-Sabbagh M, et al. Toll-like receptors in lymphoid malignancies: double-edged sword. Crit Rev Oncol Hematol. 2014;89(2):262–83. doi: 10.1016/j.critrevonc.2013.08.010.
4. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012;12(5):335–48. doi: 10.1038/nrc3257.
5. Walker BA, Boyle EM, Wardell CP, et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol. 2015;33(33):3911–20. doi: 10.1200/JCO.2014.59.1503.
6. Boyd KD, Ross FM, Chiecchio L, et al. A novel prognostic model in myeloma based on cosegregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia. 2012;26(2):349–55. doi: 10.1038/leu.2011.204.
7. Avet-Loiseau H, Durie BG, Cavo M, et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project. Leukemia. 2013;27(3):711–7. doi: 10.1038/leu.2012.282.
8. Klein U, Jauch A, Hielscher T, et al. Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone. Cancer. 2011;117(10):2136–44. doi: 10.1002/cncr.25775.
9. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–48. doi: 10.1016/S1470-2045(14)70442-5.
10. Walker BA, Wardell CP, Johnson DC, et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood. 2013;121(17):3413–9. doi: 10.1182/blood-2012-12-471888.
11. Ross FM, Avet-Loiseau H, Ameye G, et al. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica. 2012;97(8):1272–7. doi: 10.3324/haematol.2011.056176.
12. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood. 2007;109(8):3489–95. doi: 10.1182/blood-2006-08-040410.
13. Avet-Loiseau H, Li C, Magrangeas F, et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol. 2009;27(27):4585–90. doi: 10.1200/JCO.2008.20.6136.
14. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101(11):4569–75. doi: 10.1182/blood-2002-10-3017.
15. Walker BA, Wardell CP, Brioli A, et al. Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients. Blood Cancer J. 2014;4(3):e191. doi: 10.1038/bcj.2014.13.
16. Walker BA, Wardell CP, Murison A, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997. doi: 10.1038/ncomms7997.
17. Jenner MW, Leone PE, Walker BA, et al. Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma. Blood. 2007;110(9):3291–300. doi: 10.1182/blood-2007-02-075069.
18. Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. Leukemia. 2009;23(10):1691–7. doi: 10.1038/leu.2009.134.
19. 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.
20. Noren E, Verma D, Soderkvist P, et al. Single nucleotide polymorphisms in MORC4, CD14, and TLR4 are related to outcome of allogeneic stem cell transplantation. Ann Transplant. 2016;21:56–67. doi: 10.12659/AOT.895389.
21. Sivula J, Cordova ZM, Tuimala J, et al. Toll-like receptor gene polymorphisms confer susceptibility to graft-versus-host disease in allogenic hematopoietic stem cell transplantation. Scand J Immunol. 2012;76(3):336–41. doi: 10.1111/j.1365-3083.2012.02737.x.
22. Elmaagacli AH, Koldehoff M, Hindahl H, et al. Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation. Transplantation. 2006;81(2):247–54. doi: 10.1097/01.tp.0000188671.94646.16.
23. Granell M, Urbano-Ispizua A, Pons A, et al. Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation. Blood. 2008;112(10):4337–42. doi: 10.1182/blood-2007-12-129247.
24. Martino A, Sainz J, Buda G, et al. Genetics and molecular epidemiology of multiple myeloma: the rationale for the IMMEnSE consortium (review). Int J Oncol. 2011;40(3):625–38. doi: 10.3892/ijo.2011.1284.
25. Назарова Е.Л., Демьянова В.Т., Шардаков В.И. и др. Ассоциации полиморфизма ряда генов врожденного иммунитета с риском развития множественной миеломы и хронического лимфолейкоза. Гематология и трансфузиология. 2016;61(4):183–9. doi: 10.18821/0234-5730/2016-61-4-183-189. [Nazarova EL, Demyanova VT, Shardakov VI, et al. Associations of polymorphism in several innate immunity genes with the risk of the development of chronic lymphoproliferative diseases. Gematologiya i transfuziologiya. 2016;61(4):183–9. doi: 10.18821/0234-5730/2016-61-4-183-189. (In Russ)]
26. Forrest MS, Skibola CF, Lightfoot TJ, et al. Polymorphisms in innate immunity genes and risk of non-Hodgkin lymphoma. Br J Haematol. 2006;134(2):180–3. doi: 10.1111/j.1365-2141.2006.06141.x.
27. Vangsted A, Klausen TW, Vogel U. Genetic variations in multiple myeloma I: effect on risk of multiple myeloma. Eur J Haematol. 2012;88(1):8–30. doi: 10.1111/j.1600-0609.2011.01700.x.
28. Rozkova D, Novotna L, Pytlik R, et al. Toll-like receptors on B-CLL cells: expression and functional consequences of their stimulation. Int J Cancer. 2010;126(5):1132–43. doi: 10.1002/ijc.24832.
29. Charlson ME, Pompei P, Ales KL, McKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987;40(5):373–83. doi: 10.1016/0021-9681(87)90171-8.
30. National Center for Biotechnology Information. Available from: http://www.ncbi.nlm.nih.gov/ (accessed 20.12.2017).
31. National Human Genome Research Institute. Available from: https://www.genome.gov/ (accessed 20.12.2017).
32. Coleman EA, Lee JY, Erickson SW, et al. GWAS of 972 autologous stem cell recipients with multiple myeloma identifies 11 genetic variants associated with chemotherapy-induced oral mucositis. Support Care Cancer. 2015;23(3):841–9. doi: 10.1007/s00520-014-2406-x.
33. Barlogie B, Gale RP. Multiple myeloma and chronic lymphocytic leukemia: parallels and contrasts. Am J Med. 1992;93(4):443–50. doi: 10.1016/0002-9343(92)90176-c.
34. Dumontet C, Landi S, Reiman T, et al. Genetic polymorphisms associated with outcome in multiple myeloma patients receiving high-dose melphalan. Bone Marrow Transplant. 2010;45(8):1316–24. doi: 10.1038/bmt.2009.335.
35. Shaffer AL, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol. 2012;30(1):565–610. doi: 10.1146/annurev-immunol-020711-075027.
36. Vangsted AJ, Klausen TW, Ruminski W, et al. The polymorphism IL-1beta 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.
37. Bolzoni M, Ronchetti D, Storti P, et al. IL21R expressing CD14+CD16+ monocytes expand in multiple myeloma patients leading to increased osteoclasts. Haematologica. 2017;102(4):773–84. doi: 10.3324/haematol.2016.153841.
38. Gordon S. Pattern recognition receptors: doubling up for the innate immune response. Cell. 2002;111(7):927–30.
39. Isaza-Correa JM, Liang Z, van den Berg A, et al. Toll-like receptors in the pathogenesis of human B cell malignancies. J Hematol Oncol. 2014;7(1):57–67. doi: 10.1186/s13045-014-0057-5.
40. Vangsted AJ, Klausen TW, Abildgaard N, et al. Single nucleotide polymorphisms in the promoter region of the IL1B gene influence outcome in multiple myeloma patients treated with high-dose chemotherapy independently of relapse treatment with thalidomide and bortezomib. Ann Hematol. 2011;90(10):1173–81. doi: 10.1007/s00277-011-1194-3.
41. Chen H, Wilkins LM, Aziz N, et al. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet. 2006;15(4):519–29. doi: 10.1093/hmg/ddi469.
42. Landvik NE, Hart K, Skaug V, et al. A specific interleukin-1B haplotype correlates with high levels of IL1B mRNA in the lung and increased risk of non-small cell lung cancer. Carcinogenesis. 2009;30(7):1186–92. doi: 10.1093/carcin/bgp122.
43. Klein B, Zhang XG, Jourdan M, et al. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood. 1989;73(2):517–26.
44. DuVillard L, Guiguet M, Casasnovas R-O, et al. Diagnostic value of serum IL-6 level in monoclonal gammopathies. Br J Haematol. 1995;89(2):243–9. doi: 10.1111/j.1365-2141.1995.tb08944.x.
45. Lu ZY, Zhang XG, Rodriguez C, et al. Interleukin-10 is a proliferation factor but not a differentiation factor for human myeloma cells. Blood. 1995;85(9):2521–7.
46. Gu ZJ, Costes V, Lu ZY, et al. Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop. Blood. 1996;88(10):3972–86.
47. Urbanska-Rys H, Wierzbowska A, Stepien H, Robak T. Relationship between circulating interleukin-10 (IL-10) with interleukin-6 (IL-6) type cytokines (IL-6), interleukin-11 (IL-11), oncostatin M (OSM) and soluble interleukin-6 (IL-6) receptor (sIL-6R) in patients with multiple myeloma. Eur Cytokine Netw 2000;11(3):443–51.
48. 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.
49. 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/s0100-879х2006005000067.
50. 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):е402–7. doi: 10.1111/ajco.12290.
51. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345–50. doi: 10.1126/science.1177319.
52. Huang SY, Lin CW, Lin HH, et al. Expression of cereblon protein assessed by immunohistochemical staining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma. Ann Hematol. 2014;93(8):1371–80. doi: 10.1007/s00277-014-2063-7.
53. Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343(6168):301–5. doi: 10.1126/science.1244851.
54. Shaffer AL, Emre NC, Lamy L, et al. IRF4 addiction in multiple myeloma. Nature. 2008;454(7201):226–31. doi: 10.1038/nature07064.
55. Lund J. Clinical studies in multiple myeloma [thesis for doctoral degree]. Karolinska Institutet; 2016.
56. Kekik C, Besisik S, Savran Oguz F, et al. Determination of cytokine gene polymorphisms in Turkish patients with multiple myeloma. Adv Mol Med. 2007;3(4):189–95. doi: 10.2399/amm.07.189.
57. Chan KF, Siegel MR, Lenardo JM. Signaling by the TNF receptor superfamily and T cell homeostasis. Immunity. 2000;13(4):419–22. doi: 10.1016/s1074-7613(00)00041-8.
58. Richardson P, Hideshima T, Anderson K. Thalidomide: emerging role in cancer medicine. Annu Rev Med. 2002;53(1):629–57. doi: 10.1146/annurev.med.53.082901.104043.
59. Sawamura M, Murakami H, Tsuchiya J. Tumor necrosis factor-alpha and interleukin 4 in myeloma cell precursor differentiation. Leuk Lymphoma. 1996;21(1–2):31–6. doi: 10.3109/10428199609067576.
60. Abildgaard N, Glerup H, Rungby J, et al. Biochemical markers of bone metabolism reflect osteoclastic and osteoblastic activity in multiple myeloma. Eur J Haematol. 2000;64(2):121–9. doi: 10.1034/j.1600-0609.2000.90074.x.
61. Turk BE, Jiang H, Liu JO. Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production. Proc Natl Acad Sci. 1996;93(15):7552–6. doi: 10.1073/pnas.93.15.7552.
62. Sampaio EP, Hernandez MO, Carvalho DS, Sarno EN. Management of erythema nodosum leprosum by thalidomide: thalidomide analogues inhibit M. leprae-induced TNF alpha production in vitro. Biomed Pharmacother. 2002;56(1):13–9. doi: 10.1016/s0753-3322(01)00147-0.
63. Neben K, Mytilineos J, Moehler TM, et al. Polymorphisms of the tumor necrosis factor-alpha gene promoter predict for outcome after thalidomide therapy in relapsed and refractory multiple myeloma. Blood. 2002;100(6):2263–5.
64. Li C, Wang G, Gao Y, et al. TNF-alpha gene promoter –238 G>A and –308 G>A polymorphisms alter risk of psoriasis vulgaris: a meta-analysis. J Invest Dermatol. 2007;127(8):1886–92. doi: 10.1038/sj.jid.5700822.
65. Wilson AG, di Giovine FS, Blakemore AI, Duff GW. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet. 1992;1(5):353. doi: 10.1093/hmg/1.5.353.
66. Pociot F, D’Alfonso S, Compasso S, et al. Functional analysis of a new polymorphism in the human TNF alpha gene promoter. Scand J Immunol. 1995;42(4):501–4. doi: 10.1111/j.1365-3083.1995.tb03686.x.
67. Morgan GJ, Adamson PJ, Mensah FK, et al. Haplotypes in the tumour necrosis factor region and myeloma. Br J Haematol. 2005;129(3):358–65. doi: 10.1111/j.1365-2141.2005.05467.x.
68. Brown EE, Lan Q, Zheng T, et al. Common variants in genes that mediate immunity and risk of multiple myeloma. Int J Cancer. 2007;120(12):2715–22. doi: 10.1002/ijc.22618.
69. Kadar K, Kovacs M, Karadi I, et al. Polymorphisms of TNF-alpha and LT-alpha genes in multiple myeloma. Leuk Res. 2008;32(10):1499–504. doi: 10.1016/j.leukres.2008.03.001.
70. Davies FE, Rollinson SJ, Rawstron AC, et al. High-producer haplotypes of tumor necrosis factor alpha and lymphotoxin alpha are associated with an increased risk of myeloma and have an improved progression-free survival after treatment. J Clin Oncol. 2000;18(15):2843–51. doi: 10.1200/JCO.2000.18.15.2843.
71. Zheng C, Huang DR, Bergenbrant S, et al. Interleukin 6, tumour necrosis factor alpha, interleukin 1beta and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma. Br J Haematol. 2000;109(1):39–45. doi: 10.1046/j.1365-2141.2000.01963.x.
72. Якупова Э.В., Гринчук О.В., Калимуллина Д.Х. и др. Молекулярно-генетический анализ полиморфизма генов интерлейкина 6 и фактора некроза опухолей альфа у больных множественной миеломой. Молекулярная биология. 2003;37(3):420–4. [Yakupova EV, Grinchuk OV, Kalimullina DKh, et al. Molecular genetic analysis of the interleukin 6 and tumor necrosis factor alpha gene polymorphisms in multiple myeloma. Molekulyarnaya biologiya. 2003;37(3):420–4. (In Russ)]
73. Du J, Yuan Z, Zhang C, et al. Role of the TNF-α promoter polymorphisms for development of multiple myeloma and clinical outcome in thalidomide plus dexamethasone. Leuk Res. 2010;34(11):1453–8. doi: 10.1016/j.leukres.2010.01.011.
74. Goyert SM, Ferrero E, Rettig WJ, et al. The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. Science. 1988;239(4839):497–500. doi: 10.1126/science.2448876.
75. Fearns C, Kravchenko VV, Ulevitch RJ, Loskutoff DJ. Murine CD14 gene expression in vivo: extramyeloid synthesis and regulation by lipopolysaccharide. J Exp Med. 1995;181(3):857–66. doi: 10.1084/jem.181.3.857.
76. Haziot A, Chen S, Ferrero E, et al. The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage. J Immunol. 1988;141(2):547–52.
77. Bazil V, Baudys M, Hilgert I, et al. Structural relationship between the soluble and membrane-bound forms of human monocyte surface glycoprotein CD14. Mol Immunol. 1989;26(7):657–62. doi: 10.1016/0161-5890(89)90048-5.
78. Pugin J, Heumann ID, Tomasz A, et al. CD14 is a pattern recognition receptor. Immunity. 1994;1(6):509–16. doi: 10.1016/1074-7613(94)90093-0.
79. Hoshino K, Takeuchi O, Kawai T, et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. 1999;162(7):3749–52.
80. Ostuni R, Zanoni I, Granucci F. Deciphering the complexity of Toll-like receptor signaling. Cell Mol Life Sci. 2010;67(24):4109–34. doi: 10.1007/s00018-010-0464-x.
81. Wright SD, Ramos RA, Tobias PS, et al. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990;249(4975):1431–3. doi: 10.1126/science.1698311.
82. da Silveira Cruz-Machado S, Carvalho-Sousa CE, Tamura EK, et al. TLR4 and CD14 receptors expressed in rat pineal gland trigger NFKB pathway. J Pineal Res. 2010;49(2):183–92. doi: 10.1111/j.1600-079x.2010.00785.x.
83. Kielian TL, Blecha F. CD14 and other recognition molecules for lipopolysaccharide: a review. Immunopharmacology. 1995;29(3):187–205. doi: 10.1016/0162-3109(95)00003-c.
84. Holmgren C, Esplin MS, Hamblin S, et al. Evaluation of the use of anti-TNF-alpha in an LPS-induced murine model. J Reprod Immunol. 2008;78(2):134–9. doi: 10.1016/j.jri.2007.11.003.
85. Sawa Y, Ueki T, Hata M, et al. LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 expression in human lymphatic endothelium. J Histochem Cytochem. 2008;56(2):97–109. doi: 10.1369/jhc.7a7299.2007.
86. Zhou H, Andonegui G, Wong CH, Kubes P. Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. J Immunol. 2009;183(8):5244–50. doi: 10.4049/jimmunol.0901309.
87. Kanatani Y, Kasukabe T, Okabe-Kado J, et al. Role of CD14 expression in the differentiation-apoptosis switch in human monocytic leukemia cells treated with 1alpha,25-dihydroxyvitamin D3 or dexamethasone in the presence of transforming growth factor beta1. Cell Growth Differ. 1999;10(10):705–12.
88. Seiffert M, Schulz A, Ohl S, et al. Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells in vitro and present at abnormally high levels in vivo. Blood. 2010;116(20):4223–30. doi: 10.1182/blood-2010-05-284505.
89. Baldini M, Lohman IC, Halonen M, et al. A Polymorphism* in the 50′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol. 1999;20(5):976–83. doi: 10.1165/ajrcmb.20.5.3494.
90. LeVan TD, Bloom JW, Bailey TJ, et al. A common single nucleotide polymorphism in the CD14 promoter decreases the affinity of Sp protein binding and enhances transcriptional activity. J Immunol. 2001;167(10):5838–44. doi: 10.4049/jimmunol.167.10.5838.
91. Hubacek JA, Rothe G, Pitha J, et al. C(-260)-> T polymorphism in the promoter of the CD14 monocyte receptor gene as a risk factor for myocardial infarction. Circulation. 1999;99(25):3218–20. doi: 10.1161/01.cir.99.25.3218.
92. Thakur KK, Bolshette NB, Trandafir C, et al. Role of toll-like receptors in multiple myeloma and recent advances. Exp Hematol. 2014;43(3):158–67. doi: 10.1016/j.exphem.2014.11.003.
93. Ellyard JI, Simson L, Parish CR. Th2-mediated anti-tumour immunity: friend or foe? Tissue Antigens. 2007;70(1):1–11. doi: 10.1111/j.1399-0039.2007.00869.x.
94. Wyllie DH, Kiss-Toth E, Visintin A, et al. Evidence for an accessory protein function for Toll-like receptor 1 in anti-bacterial responses. J Immunol. 2000;165(12):7125–32. doi: 10.4049/jimmunol.165.12.7125.
95. Abdi J, Mutis T, Garssen J, Redegeld F. Characterization of the Toll-like receptor expression profile in human multiple myeloma cells. PLoS One. 2013;8(4):e60671. doi: 10.1371/journal.pone.0060671.
96. Bao H, Lu P, Li Y, et al. Triggering of toll-like receptor-4 in human multiple myeloma cells promotes proliferation and alters cell responses to immune and chemotherapy drug attack. Cancer Biol Ther. 2011;11(1):58–67. doi: 10.4161/cbt.11.1.13878.
97. Ramaiah SK, Gunthner R, Lech M, Anders HJ. Toll-like receptor and accessory molecule mRNA expression in humans and mice as well as in murine autoimmunity, transient inflammation, and progressive fibrosis. Int J Mol Sci. 2013;14(7):13213–30. doi: 10.3390/ijms140713213.
98. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45. doi: 10.1016/S0140-6736(00)04046-0.
99. Dorner M, Brandt S, Tinguely M, et al. Plasma cell toll-like receptor (TLR) expression differs from that of B cells, and plasma cell TLR triggering enhances immunoglobulin production. Immunology. 2009;128(4):573–9. doi: 10.1111/j.1365-2567.2009.03143.x.
100. Brown LM, Gridley G, Check D, Landgren O. Risk of multiple myeloma and monoclonal gammopathy of undetermined significance among white and black male United States veterans with prior autoimmune, infectious, inflammatory, and allergic disorders. Blood. 2008;111(7):3388–94. doi: 10.1182/blood-2007-10-121285.
101. Landgren O, Rapkin JS, Mellemkjaer L, et al. Respiratory tract infections in the pathway to multiple myeloma: a population-based study in Scandinavia. Haematologica. 2006;91(12):1697–700.
102. Huang B, Zhao J, Unkeless JC, et al. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene. 2008;27(2):218–24. doi: 10.1038/sj.onc.1210904.
103. Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer. 2009;9(1):57–63. doi: 10.1038/nrc2541.
104. Chiron D, Bekeredjian-Ding I, Pellat-Deceunynck C, et al. Toll-like receptors: lessons to learn from normal and malignant human B cells. Blood. 2008;112(6):2205–13. doi: 10.1182/blood-2008-02-140673.
105. Chiron D, Jego G, Pellat-Deuceunynck C. Toll-like receptors: expression and involvement in multiple myeloma. Leuk Res. 2010;34(12):1545–50. doi: 10.1016/j.leukres.2010.06.002.
106. Manier S, Sacco A, Leleu X, et al. Bone marrow microenvironment in multiple myeloma progression. J Biomed Biotechnol. 2012;2012:1–5. doi: 10.1155/2012/157496.
107. Bohnhorst J, Rasmussen T, Moen SH, et al. Toll-like receptors mediate proliferation and survival of multiple myeloma cells. Leukemia. 2006;20(6):1138–44. doi: 10.1038/sj.leu.2404225.
108. Xu Y, Zhao Y, Huang H, et al. Expression and function of toll-like receptors in multiple myeloma patients: toll-like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor-κB. Br J Haematol. 2010;150(5):543–53. doi: 10.1111/j.1365-2141.2010.08284.x.
109. Hajishengallis G. Toll gates to periodontal host modulation and vaccine therapy. Periodontol 2000. 2009;51(1):181–207. doi: 10.1111/j.1600-0757.2009.00304.x.
110. Щебляков Д.В., Логунов Д.Ю., Тухватулин А.И. и др. Тoлл-подобные рецепторы (TLR) и их значение в опухолевой прогрессии Acta Naturae. 2010;2(3):21–9.[Shcheblyakov DV, Logunov DY, Tukhvatulin AI, et al. Toll-like receptors (TLRs): the role in tumor progression. Acta Naturae. 2010;2(3):21–9. (In Russ)]
111. Jego G, Bataille R, Geffroy-Luseau A, et al. Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors. Leukemia. 2006;20(6):1130–7. doi: 10.1038/sj.leu.2404226.
112. Clark AD, Shetty A, Soutar R. Renal failure and multiple myeloma: pathogenesis and treatment of renal failure and management of underlying myeloma. Blood Rev. 1999;13(2):79–90. doi: 10.1016/s0268-960x(99)90014-0.
113. Wolska A, Lech-Maranda E, Robak T. Toll-like receptors and their role in hematologic malignancies. Curr Mol Med. 2009;9(3):324–35. doi: 10.2174/156652409787847182.
114. Blade J, Kyle RA, Greipp PR. Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years. Br J Haematol. 2003;93(2):345–51. doi: 10.1046/j.1365-2141.1996.5191061.x.
115. Griniute R, Bumblyte IA. Clinical and laboratory features and prognostic implications in myeloma with and without renal impairment. Medicina (Kaunas). 2003;39(Suppl 1):41–7.
116. Schroder NW, Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis. 2005;5(3):156–64. doi: 10.1016/S1473-3099(05)01308-3.
117. Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25(2):187–91. doi: 10.1038/76048.
118. Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with Gram-negative septic shock. Arch Intern Med. 2002;162(9):1028–32. doi: 10.1001/archinte.162.9.1028.
119. Netea MG, Wijmenga C, O’Neill LAJ. Genetic variation in Toll-like receptors and disease susceptibility. Nat Immunol. 2012;13(6):535–42. doi: 10.1038/ni.2284.
120. Saini M, Das DK, Dhara A, Gupta PK. Recent developments in patents targeting Toll-like receptor genes. Recent Pat DNA Gene Seq. 2007;1(3):227–39. doi: 10.2174/187221507782360263.
121. Noreen M, Arshad M. Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility. Immunol Res. 2015;62(2):234–52. doi: 10.1007/s12026-015-8640-6.
122. Goutaki M, Haidopoulou K, Pappa S, et al. The role of TLR4 and CD14 polymorphisms in the pathogenesis of respiratory syncytial virus bronchiolitis in Greek infants. Int J Immunopathol Pharmacol. 2014;27(4):563–72. doi: 10.1177/039463201402700412.
123. Apetoh L, Ghiringhelli F, Tesniere A, et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev. 2007;220(1):47–59. doi: 10.1111/j.1600-065X.2007.00573.x.
124. Bagratuni T, Terpos E, Eleutherakis-Papaiakovou E, et al. TLR4/TIRAP polymorphisms are associated with progression and survival of patients with symptomatic myeloma. Br J Haematol. 2016;172(1):44–7. doi: 10.1111/bjh.13786.
125. Awasthi S. Toll-like receptor-4 modulation for cancer immunotherapy. Front Immunol. 2014;5:328. doi: 10.3389/fimmu. 2014.00328.
126. Zhang K, Zhou B, Wang Y, et al. The TLR4 gene polymorphisms and susceptibility to cancer: a systematic review and meta-analysis. Eur J Cancer. 2013;49(4):946–54. doi: 10.1016/j.ejca.2012.09.022.
127. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21(1):335–76. doi: 10.1146/annurev.immunol.21.120601.141126.
128. He J-F, Jia W-H, Fan Q, et al. Genetic polymorphisms of TLR3 are associated with nasopharyngeal carcinoma risk in Cantonese population. BMC Cancer. 2007;7(1):194. doi: 10.1186/1471-2407-7-194.
129. Gomaz A, Pavelic J, Matijevic Glavan T. The polymorphisms in Toll-like receptor genes and cancer risk. Periodicum Biologorum. 2012;114(4):461–9.
130. Wang BG, Yi DH, Liu YF. TLR3 gene polymorphisms in cancer: a systematic review and meta-analysis. Chinese J Cancer. 2015;34(6):272–84. doi: 10.1186/s40880-015-0020-z.
131. Castrof A, Forsti A, Buch S, et al. TLR-3 polymorphism is an independent prognostic marker for stage II colorectal cancer. Eur J Cancer. 2011;47(8):1203–10. doi: 10.1016/j.ejca.2010.12.011.
132. Singh V, Srivastava N, Kapoor R, Mittal RD. Single-nucleotide polymorphisms in genes encoding Toll-like receptor-2, -3, -4, and -9 in a case-control study with bladder cancer susceptibility in a North Indian population. Arch Med Res. 2013;44(1):54–61. doi: 10.1016/j.arcmed.2012.10.008.
133. Mandal RK, George GP, Mittal RD. Association of Toll-like receptor (TLR) 2, 3 and 9 genes polymorphism with prostate cancer risk in North Indian population. Mol Biol Rep. 2012;39(7):7263–9. doi: 10.1007/s11033-012-1556-5.
134. Pandey S, Mittal B, Srivastava M, et al. Evaluation of Toll-like receptors 3 (c.1377C/T) and 9 (G2848A) gene polymorphisms in cervical cancer susceptibility. Mol Biol Rep. 2011;38(7):4715–21. doi: 10.1007/s11033-010-0607-z.
135. Etokebe GE, Knezevic J, Petricevic B, et al. Single-nucleotide polymorphisms in genes encoding toll-like receptor-2, -3, -4, and -9 in case-control study with breast cancer. Genet Test Mol Biomarkers. 2009;13(6):729–34. doi: 10.1089/gtmb.2009.0045.
136. Li G, Zheng Z. Toll-like receptor 3 genetic variants and susceptibility to hepatocellular carcinoma and HBV-related hepatocellular carcinoma. Tumour Biol. 2013;34(3):1589–94. doi: 10.1007/s13277-013-0689-z.
137. Elmaagacli AH, Koldehoff M, Beelen DW. Improved outcome of hematopoietic SCT in patients with homozygous gene variant of Toll-like receptor 9. Bone Marrow Transplant. 2009;44(5):295–302. doi: 10.1038/bmt.2009.32.
138. Lin MT, Storer B, Martin PJ, et al. Relation of an interleukin-10 promotor polymorphism to graft-versus-host disease and survival after hematopoietic cell transplantation. N Engl J Med. 2003;349(23):2201–10. doi: 10.1056/NEJMoa022060.
139. Elmaagacli AH, Koldehoff M, Steckel NK, et al. Cytochrome P450 2C19 loss-of function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation. Bone Marrow Transplant. 2007;40(7):659–64. doi: 10.1038/sj.bmt.1705786.
140. Elmaagacli AH, Koldehoff M, Landt O, Beelen DW. Relation of an Interleukin-23 Receptor gene polymorphism to Graft-versus-Host Disease after Hematopoietic-Cell Transplantation. Bone Marrow Transplant. 2008;41(9):821–6. doi: 10.1038/sj.bmt.1705980.
141. Rybka J, Gebura K, Wrobel T, et al. Variations in genes involved in regulation of the nuclear factor-κB pathway and the risk of acute myeloid leukaemia. Int J Immunogenet. 2016;43(2):101–6. doi: 10.1111/iji.12255.