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Cytokine levels in patients with non-M3 myeloid leukemia are key indicators of how well the disease responds to chemotherapy

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Abstract

Acute myeloid leukemia (AML) is a malignant hematological neoplastic disease. Autocrine or paracrine cytokines released by leukemic cells regulate the proliferation of AML cells. It is uncertain whether cytokines can indicate whether patients with AML are in remission with chemotherapy. The goal of this study was to evaluate the levels of Th1/Th2/Th17 cytokines in AML patients before and after chemotherapy to determine whether the cytokine levels could predict disease remission after chemotherapy. It was found that the levels of IL-5, IL-6, IL-8, IL-10, TNF-α, TNF-β, IL-17F, and IL-22 were significantly increased at the time of AML diagnosis in patients who achieved remission after two chemotherapy treatments (P < 0.05). After chemotherapy, the cytokine levels were reduced in patients with remission, while the levels of IL-6 and IL-8 were raised in patients without remission (P < 0.05). A comparison of cytokine levels before and after chemotherapy in patients who achieved remission showed areas under the curve (AUCs) of 0.69 for both IL-6 and IL-8. In addition, a comparison of the remission and non-remission groups after chemotherapy showed an AUC of 0.77 for IL-6. We then calculated the cutoff value using receiver operating characteristic curves. Values of IL-6 < 9.99 and IL-8 < 8.46 at the time of diagnosis were predictive of chemotherapy success and remission, while IL-6 > 14.89 at diagnosis suggested that chemotherapy would not be successful and remission would not be achieved. Multifactorial analysis showed that age, Neu, IL-6, and IL-8 were independent risk factors for AML prognosis, and IL-6 (OR = 5.48, P = 0.0038) was superior to age (OR = 3.36, P = 0.0379), Neu (OR = 0.28, P = 0.0308), IL-8 (OR = 0.0421, P = 0.0421). In conclusion, IL-6 levels were found to be predictive of the likelihood of remission.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors upon reasonable request.

References

  1. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Copplestone JA, Smith AG, Osmond C, et al. Treatment of acute myeloid leukemia in the elderly: a clinical dilemma. Hematol Oncol. 1989;7(1):53–9.

    CAS  PubMed  Google Scholar 

  3. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–52.

    PubMed  Google Scholar 

  4. Feldman EJ. Novel therapeutics for therapy-related acute myeloid leukemia: 2014. Clin Lymphoma Myeloma Leuk. 2015;15(Suppl):S91-93.

    PubMed  Google Scholar 

  5. Jakovic L, Bogdanovic A, Djordjevic V, et al. The predictive value of morphological findings in early diagnosis of acute myeloid leukemia with recurrent cytogenetic abnormalities. Leuk Res. 2018;75:23–8.

    PubMed  Google Scholar 

  6. Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378(13):1189–99.

    CAS  PubMed  Google Scholar 

  7. Jeyakumar D, O’brien S. Minimal residual disease in acute myeloid leukemia. JAMA Oncol. 2020;6(12):1899–900.

    PubMed  Google Scholar 

  8. Karimdadi Sariani O, Eghbalpour S, Kazemi E, et al. Pathogenic and therapeutic roles of cytokines in acute myeloid leukemia. Cytokine. 2021;142:155508.

    CAS  PubMed  Google Scholar 

  9. Carey A, Edwards DKT, Eide CA, et al. Identification of interleukin-1 by functional screening as a key mediator of cellular expansion and disease progression in acute myeloid leukemia. Cell Rep. 2017;18(13):3204–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Oster W, Cicco NA, Klein H, et al. Participation of the cytokines interleukin 6, tumor necrosis factor-alpha, and interleukin 1-beta secreted by acute myelogenous leukemia blasts in autocrine and paracrine leukemia growth control. J Clin Investig. 1989;84(2):451–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Leary AG, Ikebuchi K, Hirai Y, et al. Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1 alpha. Blood. 1988;71(6):1759–63.

    CAS  PubMed  Google Scholar 

  12. Vijay V, Miller R, Vue GS, et al. Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia. Leuk Res. 2019;84:106180.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Cook EB, Stahl JL, Lowe L, et al. Simultaneous measurement of six cytokines in a single sample of human tears using microparticle-based flow cytometry: allergics vs. non-allergics. J Immunol Methods. 2001;254(1–2):109–18.

    CAS  PubMed  Google Scholar 

  14. Miyawaki S, Sakamaki H, Ohtake S, et al. A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus three courses of standard-dose consolidation with maintenance therapy in adults with acute myeloid leukemia: the Japan Adult Leukemia Study Group AML 97 Study. Cancer. 2005;104(12):2726–34.

    CAS  PubMed  Google Scholar 

  15. Marumo A, Wakita S, Morita K, et al. NPM1-mutation-based measurable residual disease assessment after completion of two courses of post-remission therapy is a valuable clinical predictor of the prognosis of acute myeloid leukemia. Int J Hematol. 2022;116(2):199–214.

    CAS  PubMed  Google Scholar 

  16. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    CAS  PubMed  Google Scholar 

  17. Hasserjian RP, Steensma DP, Graubert TA, et al. Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia. Blood. 2020;135(20):1729–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. De Lima MC, Da Silva DB, Freund AP, et al. Acute Myeloid Leukemia: analysis of epidemiological profile and survival rate. J Pediatr. 2016;92(3):283–9.

    Google Scholar 

  19. Sun YX, Kong HL, Liu CF, et al. The imbalanced profile and clinical significance of T helper associated cytokines in bone marrow microenvironment of the patients with acute myeloid leukemia. Hum Immunol. 2014;75(2):113–8.

    CAS  PubMed  Google Scholar 

  20. Wang Y, Wang H, Wang W, et al. Prognostic value of platelet recovery degree before and after achieving minimal residual disease negative complete remission in acute myeloid leukemia patients. BMC Cancer. 2020;20(1):732.

    PubMed  PubMed Central  Google Scholar 

  21. Sun Y, Zhang F, Huo L, et al. Clinical characteristics and prognostic analysis of acute myeloid leukemia patients with PTPN11 mutations. Hematology (Amsterdam, Netherlands). 2022;27(1):1184–90.

    PubMed  Google Scholar 

  22. Ma JL, Zhou AQ, Gu SY, et al. Clinical and cytogenetical characteristics in acute myeloid leukemia with myelodysplasia-related changes. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021;29(6):1757–62.

    PubMed  Google Scholar 

  23. Yao X, Huang J, Zhong H, et al. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014;141(2):125–39.

    CAS  PubMed  Google Scholar 

  24. Sepehrizadeh Z, Mohammadi M, Emami A, et al. Assessment of cytokine expression profile in acute myeloid leukemia patients before and after chemotherapy. Turk J Haematol. 2014;31(2):149–54.

    PubMed  PubMed Central  Google Scholar 

  25. Kishimoto T. The biology of interleukin-6. Blood. 1989;74(1):1–10.

    CAS  PubMed  Google Scholar 

  26. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830–5.

    CAS  PubMed  Google Scholar 

  27. Li Z, Yang Z, Hu P, et al. cytokine expression of lung bacterial infection in newly diagnosed adult hematological malignancies. Front Immunol. 2021;12:748585.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang L, Zhang J, He H, et al. Increased cytokine levels assist in the diagnosis of respiratory bacterial infections or concurrent bacteremia in patients with non-Hodgkin’s lymphoma. Front Cell Infect Microbiol. 2022;12:860526.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Naugler WE, Karin M. The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med. 2008;14(3):109–19.

    CAS  PubMed  Google Scholar 

  30. Sansone P, Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human malignancies. J Clin Oncol. 2012;30(9):1005–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer (Oxford, England: 1990). 2010;46(7):1223–31.

    CAS  PubMed Central  Google Scholar 

  32. Van Der Schoot CE, Jansen P, Poorter M, et al. Interleukin-6 and interleukin-1 production in acute leukemia with monocytoid differentiation. Blood. 1989;74(6):2081–7.

    PubMed  Google Scholar 

  33. Koistinen P, Säily M, Poromaa N, et al. Complex effects of interleukin 6 on clonogenic blast cell growth in acute myeloblastic leukemia. Acta Haematol. 1997;98(1):14–21.

    CAS  PubMed  Google Scholar 

  34. Wu C, Wang S, Wang F, et al. Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol. 2009;158(2):199–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008;14(21):6735–41.

    CAS  PubMed  Google Scholar 

  36. Reikvam H, Hatfield KJ, Fredly H, et al. The angioregulatory cytokine network in human acute myeloid leukemia - from leukemogenesis via remission induction to stem cell transplantation. Eur Cytokine Netw. 2012;23(4):140–53.

    CAS  PubMed  Google Scholar 

  37. Bruserud Ø, Glenjen N, Ryningen A. Effects of angiogenic regulators on in vitro proliferation and cytokine secretion by native human acute myelogenous leukemia blasts. Eur J Haematol. 2003;71(1):9–17.

    CAS  PubMed  Google Scholar 

  38. De Bont ES, Vellenga E, Molema G, et al. A possible role for spontaneous interleukin-8 production by acute myeloid leukemic cells in angiogenesis related processes: work in progress. Med Pediatr Oncol. 2001;37(6):511–7.

    PubMed  Google Scholar 

  39. Feng L, Qi Q, Wang P, et al. Serum levels of IL-6, IL-8, and IL-10 are indicators of prognosis in pancreatic cancer. J Int Med Res. 2018;46(12):5228–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Sanguinete MMM, Oliveira PH, Martins-Filho A, et al. Serum IL-6 and IL-8 correlate with prognostic factors in ovarian cancer. Immunol Invest. 2017;46(7):677–88.

    CAS  PubMed  Google Scholar 

  41. Sanmamed MF, Carranza-Rua O, Alfaro C, et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin Cancer Res. 2014;20(22):5697–707.

    CAS  PubMed  Google Scholar 

  42. Zhu YM, Webster SJ, Flower D, et al. Interleukin-8/CXCL8 is a growth factor for human lung cancer cells. Br J Cancer. 2004;91(11):1970–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhai J, Shen J, Xie G, et al. Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer. Cancer Lett. 2019;454:37–43.

    CAS  PubMed  Google Scholar 

  44. Cheng M, Cai W, Huang W, et al. Histone deacetylase 6 regulated expression of IL-8 is involved in the doxorubicin (Dox) resistance of osteosarcoma cells via modulating ABCB1 transcription. Eur J Pharmacol. 2018;840:1–8.

    CAS  PubMed  Google Scholar 

  45. Ouyang W, Rutz S, Crellin NK, et al. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol. 2011;29:71–109.

    CAS  PubMed  Google Scholar 

  46. Saraiva M, Vieira P, O’garra A. Biology and therapeutic potential of interleukin-10. J Exp Med. 2020;217(1):e20190418.

    PubMed  Google Scholar 

  47. Li Z, Liu J, Man Y, et al. Analysis of cytokine risk factors in the early death of patients with secondary phagocytic lymphocytic histiocytosis. Am J Transl Res. 2021;13(4):2388–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kornblau SM, Mccue D, Singh N, et al. Recurrent expression signatures of cytokines and chemokines are present and are independently prognostic in acute myelogenous leukemia and myelodysplasia. Blood. 2010;116(20):4251–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Park HH, Kim M, Lee BH, et al. Intracellular IL-4, IL-10, and IFN-gamma levels of leukemic cells and bone marrow T cells in acute leukemia. Ann Clin Lab Sci. 2006;36(1):7–15.

    CAS  PubMed  Google Scholar 

  50. Tsimberidou AM, Estey E, Wen S, et al. The prognostic significance of cytokine levels in newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndromes. Cancer. 2008;113(7):1605–13.

    PubMed  Google Scholar 

  51. Sanchez-Correa B, Bergua JM, Campos C, et al. Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine. 2013;61(3):885–91.

    CAS  PubMed  Google Scholar 

  52. Yoon JY, Lafarge S, Dawe D, et al. Association of interleukin-6 and interleukin-8 with poor prognosis in elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53(9):1735–42.

    CAS  PubMed  Google Scholar 

  53. Watari K, Tojo A, Nagamura-Inoue T, et al. Hyperfunction of neutrophils in a patient with BCR/ABL negative chronic myeloid leukemia: a case report with in vitro studies. Cancer. 2000;89(3):551–60.

    CAS  PubMed  Google Scholar 

  54. Wierda WG, Johnson MM, Do KA, et al. Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukaemia. Br J Haematol. 2003;120(3):452–6.

    PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (82060810), Yunnan Provincial Department of Science and Technology- Kunming Medical University Joint Special Project on Applied Basic Research (202101AY070001-027,202201AY070001-230 and 202301AY070001-064) and Open Project of Yunnan Blood Clinical Medical Center (2022LCZXKF-XY11, 2021LCZXXF-XY09 and 2022LCZXKF-XY01).

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  1. Rui Hu and Xiaosui Ling have contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China

    Rui Hu, Xiaosui Ling, Tonghua Yang, Jinping Zhang, Xuezhong Gu, Fan Li, Yan Wen, Zengzheng Li, Yunlian Zou & Yunyun Du

  2. Yunnan Province Clinical Center for Hematologic Disease, The First People’s Hospital of Yunnan Province, Kunming, China

    Rui Hu, Xiaosui Ling, Tonghua Yang, Jinping Zhang, Xuezhong Gu, Fan Li, Yan Wen, Zengzheng Li, Yunlian Zou & Yunyun Du

  3. Yunnan Blood Disease Hospital, The First People’s Hospital of Yunnan Province, Kunming, China

    Rui Hu, Xiaosui Ling, Tonghua Yang, Jinping Zhang, Xuezhong Gu, Fan Li, Yan Wen, Zengzheng Li, Yunlian Zou & Yunyun Du

  4. Yunnan Province Clinical Research Center for Hematologic Disease, The First People’s Hospital of Yunnan Province, Kunming, China

    Rui Hu, Xiaosui Ling, Tonghua Yang, Jinping Zhang, Xuezhong Gu, Fan Li, Yan Wen, Zengzheng Li, Yunlian Zou & Yunyun Du

  5. The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China

    Heng Chen

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  1. Rui Hu
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Contributions

RH proposed the idea, participated in drafting and correcting the manuscript, and provided part of the funding support. XL drafted the manuscript and created the figures and tables. TY, JZ, HC, and XG reviewed and tallied the data. YW and JZ conducted the follow-up visits. FL and YZ performed the correction of the data. ZL performed the calculation of the results and participated in the proposal of the study. YD was the chief architect for the conduct of the project and also provided the majority of the grant funding.

Corresponding authors

Correspondence to Zengzheng Li, Yunlian Zou or Yunyun Du.

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Conflict of interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Institutional review board statement

The "Helsinki Declaration" and the "International Code of Ethics for Biomedical Research Involving Humans," developed jointly by the Council of International Medical Science Organizations and WHO as well as the related standards of the Ethics Committee of Yunnan Province's First People's Hospital, were strictly obeyed throughout this study (Number: KHLL2022-KY075).

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Patient consent was waived by the Ethics Committee of Yunnan Province's First People's Hospital due to the retrospective nature of the study.

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Hu, R., Ling, X., Yang, T. et al. Cytokine levels in patients with non-M3 myeloid leukemia are key indicators of how well the disease responds to chemotherapy. Clin Exp Med 23, 4623–4632 (2023). https://doi.org/10.1007/s10238-023-01242-7

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