ЦИТОКИНЫ ПРИ ОСТРЫХ МИЕЛОИДНЫХ ЛЕЙКОЗАХ

Цитокины являются неотъемлемой частью нормального кроветворения и оказывают влияние практически на все его этапы, вызывая и регулируя процессы клеточной пролиферации, дифференцировки и апоптоза. Благодаря исследованиям последних лет удалось показать, что цитокины являются также медиаторами сложных взаимоотношений между кроветворной, иммунной системами и растущей опухолью. С одной стороны, цитокины принимают участие в активации противоопухолевого иммунитета, направленного на элиминацию злокачественных клеток, с другой стороны, синтезируются опухолевыми клетками и участвуют в прогрессии и метастазировании опухолей. В статье обобщены данные современной литературы, касающиеся особенностей изменения цитокинового профиля у больных острыми миелоидными лейкозами (ОМЛ). Показана роль цитокинов в лейкемогенезе: в активации путей передачи сигнала, взаимодействии с костномозговым микроокружением, осуществлении противоопухолевого иммунитета и поддержании персистирования клона бластных клеток. Освещена связь отдельных цитокинов с результатами лечения и прогнозом заболевания, в том числе в зависимости от наличия в генотипе пациента различных аллельных вариантов генов цитокинов, кодирующих высокую или низкую продукцию данных факторов. Приведенные в обзоре данные об участии цитокинов в становлении, развитии и элиминации опухолевых клеток при гемобластозах подчас противоречивы, однако эти противоречия может объяснить концепция иммуноредактирования опухолей, согласно которой клетки иммунной системы в процессе канцерогенеза могут трансформироваться опухолью и начать активно содействовать ее росту. В статье использовано 69 источников литературы, в том числе 9 отечественных и 60 зарубежных, представленных в следующих информационных системах: PubMed, Scopus, Web of Science, РИНЦ.

1. Кадагидзе ЗГ. Цитокины. Практическая онкология. 2003;4:131—9.

2. Кетлинский СА, Симбирцев АС. Цитокины. Фолиант. СПб; 2008.

3. Чечина ОЕ, Биктасова АК, Сазонова ЕВ, Жукова ОБ, Прохоренко ТС, Крат ИВ и др. Роль цитокинов в редокс-зависимой регуляции апоптоза. Бюллетень сибирской медицины. 2009;8:67—72.

4. Лысенко ОВ, Занько СН. Цитокины и sFAS-лиганд при гиперпластических процессах и полипах эндометрия. Проблемы репродукции. 2010;5:31—5.

5. Симбирцев АС. Цитокины: классификация и биологические функции. Цитокины и воспаление. 2004;3:16—22.

6. Фрейдлин ИС, Тотолян АА. Клетки иммунной системы III—IV. Наука. СПб.; 2001.

7. Примак СВ, Матлан ВЛ, Барилка ВА, Шалай ОА, Логинский ВЕ. Фактор некроза опухолей при остром лейкозе. Онкология. 2015;17:17—21.

8. Азнабаева ЛФ, Плотникова СВ, Сафуанова ГШ. Предикторы системного воспаления у больных острым лейкозом. Российский иммунологический журнал. 2014;8:499—502.

9. Лубкова ОН, Цветаева НВ, Момотюк КС, Белкин ВМ, Манакова ТЕ. Экспрессия VCAM-1 на стромальных клетках из костного мозга больных миелодиспластическими синдромами. Бюл. эксп. биол. мед. 2011;151:17—20.

10. Остальные источники см. в References.

11. References

12. Carswell E, Old L, Kassel R. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Nat Acad Sci USA. 1975;72:3666—70.

13. Cohen S, Bigazzi PE, Yoshida T. Similarities of T cell function in cellmediated immunity and antibody production. Cellular Immunology. 1974;12:150—59. https://doi.org/10.1016/0008-8749(74)90066-5

14. Kadagidze ZG. Cytokines. Prakticheskaja Оnkologija. 2003;4:131—9 (in Russian).

15. Ketlinskiy SA, Simbirtsev AS. Cytokines. Foliant. St.Petersburg; 2008 (in Russian).

16. Chechina OYe, Biktasova AK, Sazonova YeV, Zhukova OB, Prokhorenko TS, Krat IV et al. The role of cytokines in redox-dependent regulation of apoptosis. Bjulleten’ Sibirskoj Meditsiny. 2009;8:67—72 (in Russian).

17. Neuhoff S, Moers J, Rieks M, Grunwald T, Jensen A, Dermietzel R et al. Proliferation, differentiation and cytokine secretion of human umbilical cord blood-derived mononuclear cells in vitro. Exp Hematol. 2007;35:1119—31.

18. Lysenko OV, Zan’ko SN. Cytokines and sFas-ligand in endometrial hyperplasia and endometrial polyps. Problemy Reproduktsii. 2010;5:31—5 (in Russian).

19. Simbirtsev AS. Cytokines — classification and biologic functions. Citokiny i Vospalenie. 2004;3:16—22 (in Russian).

20. Hebenstreit D, Horejs-Hoeck J, Duschl A. JAK/STAT-dependent gene regulations by cytokines. Drug News Perspect. 2005;18:243—9. DOI:10.1358/dnp.2005.18.4.908658

21. Freydlin IS, Totolyan AA. Cells of the immune system III—IV. Nauka. St. Petersburg; 2001 (in Russian).

22. Kupsa T, Horacek J, Jebavy L. The role of cytokines in acute myeloid leukemia: a systematic review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012;156:291—301.

23. Zeh H, Winikoff S, Landsittel D, Gorelik E, Marrangoni A, Velikokhatnaya L. Multianalyte profiling of serum cytokines for detection of pancreatic cancer. Cancer Biomark. 2005;1:259—69.

24. Kornblau S, Tibes R, Qiu Y, Chen W, Kantarjian H, Andreeff M et al. Functional proteomic profiling of AML predicts response and survival. Blood. 2009;113:154—64.

25. Brenner A, Tvedt T, Nepstad I, Rye K, Hagen K, Reikvam H et al. Patients with acute myeloid leukemia can be subclassified based on the constitutive cytokine release of the leukemic cells; the possible clinical relevance and the importance of cellular iron metabolism. Exp Opin Ther Targets. 2017;21:357—69.

26. Van Etten R, Baker S, Rane S, Reddy E. Aberrant cytokine signaling in leukemia. Oncogene. 2007;26:6738—49.

27. Birkenkamp K, Esselink M, Kruijer W, Vellenga E. Differential effects of interleukin-3 and interleukin-1 on the proliferation and interleukin-6 protein secretion of acute myeloid leukemic cells; the involvement of ERK, p38 and STAT5. Eur Cytokine Netw. 1999;10:479—90.

28. Carey A, Edwards D, Eide C, Newell L, Traer E, Medeiros B et al. Identification of interleukin-1 by functional screening as a key mediator of cellular expansion and disease progression in acute myeloid leukemia. Cell Reports. 2017;18:3204—18. doi:10.1016/j.celrep.2017.03.018

29. Meyers C, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer. 2005;104:788—93.

30. Kupsa T, Vasatova M, Karesova I, Zak P, Horacek JM. Baseline serum levels of multiple cytokines and adhesion molecules in patients with acute myeloid leukemia: results of a pivotal trial. Exp Oncol. 2014;36:252—7.

31. Hsu H, Lee Y, Tsai W, Jiang M, Ho CH, Ho CK et al. Circulating levels of thrombopoietic and inflammatory cytokines in patients with acute myeloblastic leukemia and myelodysplastic syndrome. Oncology. 2002;63:64—9.

32. Primak SV, Matlan VL, Barilka VA, Shalay OA, Loginskiy VE. The tumor necrosis factor in acute leukemia. Oncology (Onkologija). 2015;17:17—21 (in Russian).

33. Panteli K, Hatzimichael E, Bouranta P, Katsaraki A, Seferiadis K, Stebbing J et al. Serum interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic myeloproliferative diseases. Br J Haematol. 2005;130:709—15.

34. Aguayo A, Kantarjian H, Estey E, Giles F, Verstovsek S, Manshouri T et al. Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes. Cancer. 2002;95:1923—30.

35. Kornblau S, McCue D, Singh N, Chen W, Estrov Z, Coombes K. Recurrent expression signatures of cytokines and chemokines are present and are independently prognostic in acute myelogenous leukemia and myelodysplasia. Blood. 2010;116:4251—61. doi: 10.1182/ blood-2010-01-262071

36. Aznabaeva LF, Plotnikova SV, Safuanova GS. Predictors of systemic inflammation in patients with acute leukemia. Russian Journal of Immunology (Rossijskij Immunologicheskij Zhurnal). 2014;17:499—502 (in Russian).

37. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of Th17 cells. Nature. 2008;453:1051—7.

38. Abousamra N, Salah El-Din M, Helal R. Prognostic value of Th17 cells in acute leukemia. Med Oncol. 2013;30:732. doi: 10.1007/s12032-013- 0732-3

39. Zhu B, Zhang J, Wang X, Chen J, Li C. Correlation between acute myeloid leukemia and IL-17A, IL-17F, and IL-23R gene polymorphism. Int J Clin Exp Pathol. 2015;8:5739—43.

40. Wu C, Wang S, Wang F, Chen Q, Peng S, Zhang Y. Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol. 2009;158:199—204.

41. Tian T, Yu S, Wang M, Yuan C, Zhang H, Ji C et al. Aberrant T helper 17 cells and related cytokines in bone marrow microenvironment of patients with acute myeloid leukemia. Clin Dev Immunol. 2013;2013:915873.

42. Ersvaer E, Liseth K, Skavland J, Gjertsen BT, Bruserud О. Intensive chemotherapy for acute myeloid leukemia differentially affects circulating TC1, TH1, TH17, and Treg cells. BMC Immunol. 2010;11:38. doi:10.1186/1471-2172-11-38

43. Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K et al. STAT3 orchestrates contradictory signals in cytokine induced G1 to S cell-cycle transition. EMBO J. 1998;17:6670—7.

44. Chaudhari S, Desai J, Adam A, Mishra P. Jak/Stat as a novel target for treatment of leukemia. Int J Pharm Pharm Sci. 2014;6:1—7.

45. Tsapogas P, Mooney C, Brown G, Rolink A. The cytokine Flt3-ligand in normal and malignant hematopoiesis. Int J Mol Sci. 2017;18:1115. doi:10.3390/ijms18061115

46. Estrov Z, Black R, Sleath P, Harris D, Van Q, LaPushin R et al. Effect of interleukin-1 beta converting enzyme inhibitor on acute myelogenous leukemia progenitor proliferation. Blood. 1995;86:4594—602.

47. Nakase K, Kita K, Kyo T, Ueda T, Tanaka I, Katayama N. Prognostic relevance of cytokine receptor expression in acute myeloid leukemia: interleukin-2 receptor α-chain (CD25) expression predicts a poor prognosis. PLOS ONE. 2015; September 16. http://journals.plos.org/ plosone/article?id=10.1371/journal.pone.0128998

48. Malek T. The biology of interleukin-2. Annu Rev Immunol. 2008;26:453— 79. doi:10.1146/annurev.immunol.26.021607.090357

49. Derolf A, Laane E, Bjorklund E, Saft L, Bjorkholm M. Dendritic cells in bone marrow at diagnosis and after chemotherapy in adult patients with acute myeloid leukemia. Scand J Immunol. 2014;80:424—31. doi/10.1111/ sji.12223/pdf

50. Nakase K, Kita K, Kyo T, Tsuji K, Katayama N. High serum levels of soluble interleukin-2 receptor in acute myeloid leukemia: correlation with poor prognosis and CD4 expression on blast cells. Cancer Epidemiol. 2012;36:e306—9. doi: 10.1016/j.canep.2012.03.011

51. Yang Z-Z, Grote D, Ziesmer S, Manske M, Witzig T. Soluble IL-2Rα facilitates IL-2-mediated immune responses and predicts reduced survival in follicular B-cell non-Hodgkin lymphoma. Blood. 2011;118:2809—20. doi: 10.1182/blood-2011-03-340885

52. Bruserud O, Foss B, Petersen H. Hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders: Studies of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and Flt-3 ligand (Flt3L). Eur Cytokine Netw. 2001;12:231—8.

53. Tajima N, Fukui K, Uesato N. JTE-607, a multiple cytokine production inhibitor, induces apoptosis accompanied by an increase in p21waf1/cip1 in acute myelogenous leukemia cells. Cancer Sci. 2010;101:774—81.

54. Tsimberidou A, Estey E, Wen S, Pierce S, Kantarjian H, Albitar M et al. The prognostic significance of cytokine levels in newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndromes. Cancer. 2008;113:1605—13.

55. Konopleva M, Jordan C. Leukemia stem cells and microenvironment: biology and therapeutic targeting. Clin Oncol. 2011;29:591—9.

56. Kupsa T, Vanek J, Zak P, Jebavy L, Horacek J. Serum levels of soluble adhesion molecules in newly diagnosed acute myeloid leukemia and in complete remission suggest endothelial cell activation by myeloblasts. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017;161:92— 9. doi: 10.5507/bp.2016.054

57. Lubkova ON, Tzvetaeva NV, Momotyuk KS, Belkin VM, Manakova TE. VCAM-1 expression on bone marrow stromal cells from patients with myelodysplastic syndromes. Bull Exp Biol Med. 2011;151:17—20 (in Russian).

58. Lopes MR, Pereira JK, de Melo Campos P, Machado-Neto JA, Traina F, Saad ST et al. De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes. Sci Rep. 2017;7:40707. doi:10.1038/srep40707

59. Skaik Y, Vahlsing S, Goudeva L, Eiz-Vesper B, Battermann A, Blasczyk R et al. Secreted beta3-integrin enhances natural killer cell activity against acute myeloid leukemia cells. PLoS ONE. 2014;9:e98936.

60. Johansen S, Brenner A, Bartaula-Brevik S, Reikvam H, Bruserud О. The possible importance of β3 integrins for leukemogenesis and chemoresistance in acute myeloid leukemia. Int J Mol Sci. 2018;19:251. doi:10.3390/ ijms19010251

61. Nishioka C, Ikezoe T, Pan B, Xu K, Yokoyama A. MicroRNA-9 plays a role in interleukin-10-mediated expression of E-cadherin in acute myelogenous leukemia cells. Cancer Sci. 2017;108:685—95. https://doi. org/10.1111/cas.13170

62. Reikvam H, Fredly H, Kittang A, Bruserud O. The possible diagnostic and prognostic use of systemic chemokine profiles in clinical medicine — the experience in acute myeloid leukemia from disease development and diagnosis via conventional chemotherapy to allogeneic stem cell transplantation. Toxins (Basel). 2013;5:336—62. doi:10.3390/toxins5020336

63. Bruserud O, Ryningen A, Olsnes AM. Subclassification of patients with acute myelogenous leukemia based on chemokine responsiveness and constitutive chemokine release by their leukemic cells. Haematologica. 2007;92:332—41.

64. Fredly H, Reikvam H, Gjertsen B, Bruserud O. Disease-stabilizing treatment with all-trans retinoic acid and valproic acid in acute myeloid leukemia: Serum hsp70 and hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti-leukemic treatment. Am J Hematol. 2012;87:368—76. doi: 10.1002/ajh.23116

65. Clarke C, Smyth M. Calreticulin exposure increases cancer immunogenicity. Nat Biotechnol. 2007;25:192—3. doi:10.1038/ nbt0207-192

66. Tilton B, Ho L, Oberlin E, Loetscher P, Baleux F, Clark-Lewis I et al. Signal transduction by CXC chemokine receptor 4. Stromal cell derived factor 1 stimulates prolonged protein kinase B and extracellular signal-regulated kinase 2 activation in T lymphocytes. J Exp Med. 2000;192:313—24.

67. Konoplev S, Rassidakis G, Estey E, Kantarijan H, Liakou C, Juany X et al. Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype. Cancer. 2007;109:1152—6.

68. Rombouts E, Pavic B, Lowenberg B, Ploemacher R. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood. 2004;104:550—7.

69. Niedermeier M, Hennessy B, Knight Z, Henneberg M, Hu J, Kurtova A et al. Isoform-selective phosphoinositide 3´-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood. 2009;113:5549—57.

70. Zheng Q, Shuai X, Ye Y, Jin Y, Jiang N, Chen X et al. The role of polymorphisms of stromal-derived factor-1 and CXC receptor 4 in acute myeloid leukemia and leukemia cell dissemination. Gene. 2016;588:103—8.

71. El-Ghany H, El-Saadany Z, Bahaa N, Ibrahim N, Hussien S. Stromal cell derived factor-1 (CXCL12) chemokine gene variant in myeloid leukemias. Clin Lab. 2014;60:735—41.

72. Wang H, Hua M, Wang S, Yu J, Chen C, Zhao X et al. Genetic polymorphisms of IL-18 rs1946518 and IL-1β rs16944 are associated with prognosis and survival of acute myeloid leukemia. Inflamm Res. 2017;66:249—58.

73. Sung L, Dix D, Cellot S, Gillmeister B, Ethier MC, Roslin NM et al. Single nucleotide polymorphism in IL-1B is associated with infection risk in paediatric acute myeloid leukaemia. Clin Microbiol Infect. 2016;22:563. e9—17.

74. Fei C, Yao XM, Sun Y, Gu XZ, Yu LQ, Lai X. Interleukin-10 polymorphisms associated with susceptibility to acute myeloid leukemia. Genet Mol Res. 2015;14:925—30.

75. Kazamatsu T, Saitoh T, Minato Yu, Shimizu H, Yokohama A, Tsukamoto N et al. Polymorphisms of IL-10 affect the severity and prognosis of myelodysplastic syndrome. Eur J Hematol. 2016;96:245—51.

76. Kim M, Kim J, Kim JR, Han E, Park J, Lim J et al. FLT3 expression and IL-10 promoter polymorphism in acute myeloid leukemia with RUNX1-RUNX1T1. Mol Biol Rep. 2015;42:451—6.

77. Wrobel T, Gebura K, Wysoczanska B, Jazwiec B, Dobrzynska O, Mazur G et al. IL-17F gene polymorphism is associated with susceptibility to acute myeloid leukemia. J Cancer Res Clin Oncol. 2014;140:1551—5. doi:10.1007/s00432-014-1674-7

78. Dunn G, Ikeda H, Bruce A, Koebel C, Uppaluri R, Bui J et al. Interferon gamma and cancer immunoediting. Immunol Res. 2005;32:231—45.

79. Teng MW, Galon J, Fridman WH, Smyth MJ. From mice to humans: developments in cancer immunoediting. J Clin Invest. 2015;125:3338—46. https://doi.org/10.1172/JCI80004

80. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunol. 2010;11:889— 96. doi:10.1038/ni.1937