Prognostic Impact of Serum Growth Differentiation Factor 15 Level in Acute Myeloid Leukemia Patients

Abstract

Growth differentiation factor 15 (GDF15) plays an important role in cancer pathophysiology and prognosis. However, limited studies analyzed its level and prognostic value in acute myeloid leukemia (AML) patients. This study included 56 adult AML patients. Serum GDF15 level was measured at diagnosis in all patients by enzyme-linked immunosorbent assay. Remission and survival statuses were assessed at 90 days following treatment. GDF15 level was significantly higher in patients than in controls (P < 0.001). GDF15 level correlated positively with age (P < 0.001), hemoglobin level (P = 0.027), and platelet count (P = 0.024). High GDF15 above the median level was associated with inferior OS (P = 0.044) together with high platelet count (P = 0.006) and high bone marrow blast percent (P = 0.038). There was no statistically significant difference between patients with GDF15 above and below the median level regarding DFS (P = 0.881). On multivariate analysis for OS, GDF15 level was an independent risk factor (P = 0.047). In conclusion, serum GDF15 level is significantly elevated in AML patients and high GDF15 level is associated with inferior OS.

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References

  1. 1.

    Bootcov MR, Bauskin AR, Valenzuela SM et al (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-superfamily. Proc Natl Acad Sci USA 94:11514–11519

    CAS  PubMed  Google Scholar 

  2. 2.

    Berezin AE (2016) Diabetes mellitus related biomarker: the predictive role of growth-differentiation factor-15. Diabetes Metab Syndr 10(1 Suppl. 1):S154–S157

    PubMed  Google Scholar 

  3. 3.

    Breit SN, Johnen H, Cook AD et al (2011) The TGF-β superfamily cytokine, MIC-1/GDF15: a pleotrophic cytokine with roles in inflammation, cancer and metabolism. Growth Factors 29:187–195

    CAS  PubMed  Google Scholar 

  4. 4.

    Mimeault M, Batra SK (2010) Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer. J Cell Physiol 224:626–635

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Buendgens L, Yagmur E, Bruensing J et al (2017) Growth differentiation factor-15 is a predictor of mortality in critically ill patients with sepsis. Dis Markers 2017:5271203

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Saultz JN, Garzon R (2016) Acute myeloid leukemia: a concise review. J Clin Med 5(3):33

    PubMed Central  Google Scholar 

  7. 7.

    Döhner K, Döhner H (2008) Molecular characterization of acute myeloid leukemia. Haematologica 93(7):976–982

    PubMed  Google Scholar 

  8. 8.

    Schlenk RF, Döhner H (2013) Genomic applications in the clinic: use in treatment paradigm of acute myeloid leukemia. Hematol Am Soc Hematol Educ Program 2013:324–330

    Google Scholar 

  9. 9.

    Uchiyama T, Kawabata H, Miura Y et al (2015) The role of growth differentiation factor 15 in the pathogenesis of primary myelofibrosis. Cancer Med 4(10):1558–1572

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976;33(4):451–458

  11. 11.

    Slovak ML, Kopecky KJ, Cassileth PA et al (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96(13):4075–4083

    CAS  PubMed  Google Scholar 

  12. 12.

    Yates J, Glidewell O, Wiernik P et al (1982) Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 60(2):454–462

    CAS  PubMed  Google Scholar 

  13. 13.

    Mayer RJ, Davis RB, Schiffer CA et al. (1994) Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331(14):896–903

    Google Scholar 

  14. 14.

    Burnett AK, Russell NH, Hills RK et al (2013) Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML 15 trial. J Clin Oncol 31(27):3360–3368

    CAS  PubMed  Google Scholar 

  15. 15.

    Medeiros BC (2018) Interpretation of clinical endpoints in trials of acute myeloid leukemia. Leuk Res 68:32–39

    PubMed  Google Scholar 

  16. 16.

    Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE (2001) Cyclooxygenase inhibitors regulate the expression of a TGF-β superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol 59(4):901–908

    CAS  PubMed  Google Scholar 

  17. 17.

    Liu T, Bauskin AR, Zaunders J et al (2003) Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells. Cancer Res 63(16):5034–5040

    CAS  PubMed  Google Scholar 

  18. 18.

    Kadara H, Schroeder CP, Lotan D, Pisano C, Lotan R (2006) Induction of GDF-15/NAG-1/MIC-1 in human lung carcinoma cells by retinoid-related molecules and assessment of its role in apoptosis. Cancer Biol Ther 5(5):518–522

    CAS  PubMed  Google Scholar 

  19. 19.

    Brown DA, Breit SN, Buring J et al (2002) Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: A nested case-control study. Lancet 359:2159–2163

    CAS  PubMed  Google Scholar 

  20. 20.

    Lankeit M, Kempf T, Dellas C et al (2008) Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism. Am J Respir Crit Care Med 177:1018–1025

    CAS  PubMed  Google Scholar 

  21. 21.

    Brown DA, Moore J, Johnen H et al. (2007) Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis. A potential marker of erosive joint destruction. Arthritis Rheum 56:753–764

    CAS  PubMed  Google Scholar 

  22. 22.

    Breit SN, Carrero JJ, Tsai VW et al (2012) Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end-stage renal disease. Nephrol Dial Transplant 27:70–75

    CAS  PubMed  Google Scholar 

  23. 23.

    Tanno T, Bhanu NV, Oneal PA et al (2007) High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13:1096–1101

    CAS  PubMed  Google Scholar 

  24. 24.

    Tamary H, Shalev H, Perez-Avraham G et al (2008) Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I. Blood 112:5241–5244

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Ramirez JM, Schaad O, Durual S et al (2009) Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts. Br J Haematol 144:251–262

    PubMed  Google Scholar 

  26. 26.

    Zhang L, Yang X, Pan H-Y et al (2009) Expression of growth differentiation factor 15 is positively correlated with histopathological malignant grade and in vitro cell proliferation in oral squamous cell carcinoma. Oral Oncol 5:627–632

    Google Scholar 

  27. 27.

    Boyle GM, Pedley J, Martyn AC et al (2009) Macrophage inhibitory cytokine-1 is overexpressed in malignant melanoma and is associated with tumorigenicity. J Invest Dermatol 129:383–391

    CAS  PubMed  Google Scholar 

  28. 28.

    Hogendorf P, Durczyński A, Skulimowski A, Kumor A, Poznańska G, Strzelczyk J (2018) Growth differentiation factor (GDF-15) concentration combined with Ca125 levels in serum is superior to commonly used cancer biomarkers in differentiation of pancreatic mass. Cancer Biomark 21(3):505–511

    CAS  PubMed  Google Scholar 

  29. 29.

    Lima CA, Jammal MP, Martins-Filho A et al (2018) Stromal growth differentiation factor 15 and its association with ovarian cancer. Gynecol Obstet Invest 83(1):35–39

    CAS  PubMed  Google Scholar 

  30. 30.

    Moore AG, Brown DA, Fairlie WD et al (2000) The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 85:4781–4788

    CAS  PubMed  Google Scholar 

  31. 31.

    Segerer SE, Rieger L, Kapp M et al (2012) MIC-1 (a multifunctional modulator of dendritic cell phenotype and function) is produced by decidual stromal cells and trophoblasts. Hum Reprod 27(1):200–209

    CAS  PubMed  Google Scholar 

  32. 32.

    Lu W, Wan Y, Li Z et al (2018) Growth differentiation factor 15 contributes to marrow adipocyte remodeling in response to the growth of leukemic cells. J Exp Clin Cancer Res 37(1):66

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Zhai Y, Zhang J, Wang H et al (2016) Growth differentiation factor 15 contributes to cancer-associated fibroblasts-mediated chemo-protection of AML cells. J Exp Clin Cancer Res 35(1):147

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Tarkun P, Mehtap O, Atesoglu EB, Geduk A, Musul MM, Hacihanefioglu A (2013) Serum hepcidin and growth differentiation factor-15 (GDF-15) levels in polycythemia vera and essential thrombocythemia. Eur J Haematol 91:228–235

    CAS  PubMed  Google Scholar 

  35. 35.

    Zhao N, Yang J (2014) Expression of serum GDF15 and its clinical significance in multiple myeloma patients. Zhong Nan Da Xue Xue Bao Yi Xue Ban 39(3):270–275

    CAS  PubMed  Google Scholar 

  36. 36.

    Corre J, Hébraud B, Bourin P (2013) Concise review: growth differentiation factor 15 in pathology: a clinical role? Stem Cells Transl Med 2(12):946–952

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Corre J, Labat E, Espagnolle N et al (2012) Bioactivity of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma. Cancer Res 72(6):1395–1406

    CAS  PubMed  Google Scholar 

  38. 38.

    Tarkun P, Birtas Atesoglu E, Mehtap O, Musul MM, Hacihanefioglu A (2014) Serum growth differentiation factor 15 levels in newly diagnosed multiple myeloma patients. Acta Haematol 131(3):173–178

    CAS  PubMed  Google Scholar 

  39. 39.

    Li C, Wang X, Casal I et al (2016) Growth differentiation factor 15 is a promising diagnostic and prognostic biomarker in colorectal cancer. J Cell Mol Med 20(8):1420–1426

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Winand FJ, Boegemann M, Gallitz I et al (2014) GDF15 and Hepcidin as prognostic factors in patients with prostate cancer. J Mol Biomark Diagn 5:6

    Google Scholar 

  41. 41.

    Staff AC, Bock AJ, Becker C, Kempf T, Wollert KC, Davidson B (2010) Growth differentiation factor-15 as a prognostic biomarker in ovarian cancer. Gynecol Oncol 118(3):237–243

    CAS  PubMed  Google Scholar 

  42. 42.

    Lerner L, Hayes TG, Tao N et al (2015) Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients. J Cachexia Sarcopenia Muscle 6(4):317–324

    PubMed  PubMed Central  Google Scholar 

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Correspondence to Amro Mohamed Sedky El-Ghammaz.

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Hegab, H.M., El-Ghammaz, A.M.S., El-Razzaz, M.K. et al. Prognostic Impact of Serum Growth Differentiation Factor 15 Level in Acute Myeloid Leukemia Patients. Indian J Hematol Blood Transfus (2020). https://doi.org/10.1007/s12288-020-01315-7

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Keywords

  • Growth differentiation factor 15
  • Acute myeloid leukemia
  • Overall survival
  • Disease free survival