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Analysis of serum levels of Dickkopf-1 (DKK-1) in monoclonal gammopathy of undetermined significance and multiple myeloma


Authors: Vlastimil Ščudla 1;  Pavla Petrová 2;  Tomáš Pika 1;  Pavel Lochman 2;  Jiří Minařík 1;  Jaroslav Bačovský 1;  Karel Srovnalík 3
Authors‘ workplace: 3. interní klinika – nefrologická, revmatologická a endokrinologická LF UP a FN, Olomouc 1;  Oddělení klinické biochemie FN, Olomouc 2;  Hematologické oddělení, Nemocnice Vsetín 3
Published in: Čas. Lék. čes. 2015; 154: 181-188
Category: Original Article

Overview

Background.
Several recent studies aim at the detection of biological parameters that enable more precise diagnostics and stratification of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). The objective of our study was to assess the potential contribution of serum levels of Dickkopf-1 (DKK-1) in MGUS and MM from the point of more specific differentiation of both conditions, and the relationship of DKK-1 to selected laboratory parameters, individual forms and clinical stages of both conditions.

Methods and results.
The analyzed cohort consisted of 46 individuals with MGUS and 152 patients with MM at the time of diagnosis. For the assessment of serum levels of DKK-1 we used ELISA method. We assessed also serum levels of free light chains (FLC) κ and λ using the Freelite system, and β2-microglobulin (β2-M ) using the Immulite 1000 method. For statistical estimation we used: Pearson χ2-test, U-test according to Mann-Whitney and Kruskal-Wallis test. Our analysis revealed that there was no significant difference between the levels of DKK-1 in MGUS risk groups (0–3) and between the states with different FLC concentration including the κ/λ index of monoclonality. In MM there was a significant relationship of DKK-1 to the level of hemoglobin (p < 0.008) but not to the levels of FLC, creatinine or β2-microglobulin. Within the Durie-Salmon staging system, there were significant differences of DKK-1 between the stages I vs. III (p = 0.001) and I vs. II + III (p = 0.002). In the International Staging System (ISS) there were significant differences only between stages 1 vs. 2 + 3 (p = 0.045). Although there was no overall significant difference of DKK-1 levels between MGUS and MM, there was a difference between MGUS vs stage III (p = 0.001) and II+III (p = 0.001) according to Durie-Salmon, and also MGUS vs. stage 2 (p = 0.005) and vs. stages 2 + 3 (p = 0,012) according to ISS. There were no significant differences in DKK-1 between MGUS and initial/asymptomatic form of MM (stage I).

Conclusion.
Although there was a significant difference of serum levels of DKK-1 between MGUS and initial/asymptomatic stage of MM when compared to advanced stage MM, and in patients with different Hb levels, we do not find the evaluation of serum levels of DKK-1 useful for routine discrimination of MGUS and MM, and for the specification of temporary stratification systems.

Keywords:
monoclonal gammopathy of undetermined significance – multiple myeloma – Dickkopf-1 (DKK-1) – MGUS stratification – multiple myeloma staging


Sources

1. Hájek R, Adam Z, Maisnar V, et al. Diagnostika a léčba mnohočetného myelomu. Doporučení České myelomové skupiny 2012. Transfuze Hematol Dnes 2012; 18(Suppl 1): 3–90.

2. Kocemba KA, Groen RW, VanAndel H, et al. Transcriptional silencing of the Wnt-antagonist DKK-1 by promoter methylation is associated with enhanced Wnt signaling in advanced multiple myeloma.PloS ONE 7(2): e30359. doi:10.1371/journal.pone 0030359.

3. Bataille R, Chappard D, Marcelli C, et al. Mechanisms of bone destruction in multiple myeloma: the importace of unbalanced process in determining the severity of lytic bone disease. J Clin Oncol 1989; 7: 1909–1914.

4. Kristensen IB, Christensen JH, Lyng MB, et al. Expression of osteoblast and osteoclast regulatory genes in the bone marrow microenviroment in multiple myeloma: only up-regulation of Wnt inhibitors SFRP3 and DKK-1 is associated with lytic bone disease. Leukemia§Lymphoma 2013: Early Online: 1–9. doi: 10.3109/10428194.2013.820288.

5. Giuliani N, Morandi F, Tagliaferri S, et al. Production of Wnt inhibitors by myeloma cells: potential effects on canonical Wnt pathway in the bone microenvironment. Cancer Res 2007; 67: 7665–7674.

6. Oshima T, Abe M, Asano J, et al. Myeloma cells supress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 2005; 106: 3160–3165.

7. Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist DKK-1 in the development of osteolytic lesions in multiple myeloma. New Engl J Med 2003; 349: 2483–2494.

8. Niehrs C. Function and biological role sof the Dickkopf family of Wnt modulators. Oncogene 2006; 25: 7469–7481.

9. Haaber J, Abildgaar N, Knudsen LM, et al. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only everexpression of DKK-1 correlates with clinical bone involvement at diagnosis. Brit J Haematol 2007; 140: 25–35.

10. Qiang YW, Barlogie B, Rudikoff S, et al. DKK-1 induced inhibition of Wnt signaling in osteoblast differentiation is an underlying mechanism of bone loss in multiple myeloma. Bone 2008; 42: 669–680.

11. Heider U, Kaiser M, Mieth M, et al. Serum concentrations of DKK-1 decrease in patiens with multiple myeloma responding to anti-myeloma treatment. Eur J Haematol 2009; 82: 31–38.

12. Qiang YW, Chen Y, Stephens O, et al. Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood 2008; 112: 196–207.

13. McDonald BT, Joiner DM,Oyserman SM, et al. Bone mass is inversely proportional to DKK-1 levels in mice. Bone 2007; 41: 331–339.

14. Manier S, Sacco A, Leleu X, et al. Bone marrow microenvironment in multiple myeloma progression. J Biomed Biotechnol. doi:10.1155/2012/157496.

15. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008; 8: 387–398.

16. Edwards CM, Edwards JR, Lwin ST, et al. Increaseing Wnt signaling in the bone marrow microenvironment inhibite the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood 2008; 111: 2832–2842.

17. Cianferotti L, Demay MB. VDR-mediated inhibition of DKK-1 a SFRP-2 supresses adipogenic differentiation of murine bone marrow stromal cells. J Cell Biochem 2007; 101: 80–88.

18. Robbiani DF, Chesi M, Bergsagel PL, et al. Bone lesions in molecular subtypes of multiple myeloma. New Engl J Med 2004; 351: 197–198.

19. Rajkumar SV, Kyle RA, Therneau (tm), et al. Serum free light chain ratio in an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005; 106: 812–817.

20. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Cancer 1975; 36: 842–854.

21. Greipp PR, San Miguel J, Durie BGM, et al. International Staging System for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420.

22. Ščudla V, Budíková M, Pika T, et al. Srovnání sérových hladin vybraných biologických působků u monoklonální gamapatie nejistého významu a mnohočetného myelomu. Čas Lék čes 2009; 148: 315–322.

23. Ščudla V, Budíková M, Petrová P, et al. Analýza sérových hladin vybraných biologických ukazatelů u monoklonální gamapatie nejistého významu a mnohočetného myelomu. Klin Onkol 2010; 23: 171–181.

24. Scudla V, Petrova P, Minarik J, et al. Analysis of the serum levels of selected biological parameters in monoclonal gammopathy of undetermined significance and different stages of multiple myeloma. Neoplasma 2011; 58: 499–506.

25. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Brit J Haematol 2003; 121: 749–757.

26. Bradwell AR. Serum free light chain analysis (plus Hevylite). 6th. ed. Birmingham: The Binding Site Ltd. 2010; 350.

27. Kaiser M, Mieth M, Liebisch P, et al. Serum concentrations of DKK-1 correlate with the extent of bone disease in patiens with multiple myeloma. Eur J Haematol 2008; 80: 490–494.

28. Zhou F, Meng S, Song H, et al. Dickkopf-1 is a key regulator of myeloma bone disease: opportunities and challenges for therapeutic intervention. Blood Rev 2013; 27: 261–267.

29. Fowler JA, Mundy GM, Lwin ST, et al. Bone marrow stromal cells create a permissive microenvironment for myeloma development: a new stromal role for Wnt inhibitor. Cancer Res 2012; 72: 2183–2189.

30. Ling L, Nurcombe V, Cool SM. Wnt signaling controls the face of mesenchymal stem cells. Gene 2009; 433: 1–7.

31. Silvestris F, Lombardi L, De Matteo M, et al. Myeloma bone disease: pathogenetic mechanisms and clinical assessment. Leuk Res 2007; 31: 129–138.

32. Pinzone IJ, Hall BM, Thudi NK, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 2009; 113: 517–525.

33. Ng AC, Khosla S, Charatcharoenwitthaya N, et al. Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography and elevated DKK-1 and MIP-1alpha levels in patiens with MGUS. Blood 2011; 118: 6529–6534.

34. Todoerti K, Lisignoli G, Storti P, et al. Distinct transcriptional profiles characterize bone microenvironment mesenchymal cells another than osteoblasts relationship with multiple myeloma bone disease. Exp Hematol 2010; 38: 141–153.

35. Politou MC, Heath DJ, Rahemtulla A, et al. Serum concentrations of Dickkopf-1 protein are increased in patiens with multiple myeloma and reduced after autologous stem cell transplantation. Int J Cancer 2006; 119: 1728–1731.

36. Colla S, Zhan F, Xiong W, et al. The oxidative stress response regulates DKK-1 expression through the JNK signaling cascade in multiple myeloma plasma cells. Blood 2007; 109: 4470–4477.

37. Wu P, Walker BA, Brewer D, et al. A gene expression-based predictor for myeloma patiens at high risk of developing bone disease on bisphonate treatment. Clin Cancer Res 2011; 17: 6347–6355.

38. Kristinsson SY,Tang M, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study. Blood 2010; 116: 2651–2655.

39. Quian J, Zheng Y, Zheng C, et al. Active vaccination with Dickkopf-1 induces protective and therapeutic antitumor imunity in murine multiple myeloma. Blood 2012; 119: 161–169.

40. Pozzi S, Fulciniti M, Yan H, et al. In vivo and in vitro effects of a novel anti DKK-1 neutralizing antibody in multiple myeloma. Bone 2013; 53: 487–496.

41. Zangari M, Terpos E, Zhan F, et al. Impact of bortezomib on bone health in myeloma: a review of current evidence. Cancer Trat Rev 2012; 38: 968–980.

42. Terpos E, Heath DJ, Rahemptulla A, et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor kappaB ligand concentrations and normalises indices of bone remodelling in patiens with relapsed multiple myeloma. Brit J Haematol 2006; 135: 688–692.

43. Yaccoby S, Ling W, Zhan F, et al. Antibody-based inhibition of DKK-1 supresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007; 109: 2106-2111.

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