Blood Res.  2017 Dec;52(4):293-299. 10.5045/br.2017.52.4.293.

STAT3 expression is associated with poor survival in non-elderly adult patients with newly diagnosed multiple myeloma

• Jung SH
• Ahn SY
• Choi HW
• Shin MG
• Lee SS
• Yang DH
• Ahn JS
• Kim YK
• Kim HJ
• Lee JJ

• KMID: 2405066
• DOI: http://doi.org/10.5045/br.2017.52.4.293

Abstract

BACKGROUND
Signal transducer and activator of transcription 3 (STAT3) is not only a key signaling molecule in the regulation of growth but is also involved in malignant transformation. We investigated the prognostic significance of STAT3 expression in 94 non-elderly adult patients (aged 38 to 65 yr) with newly diagnosed multiple myeloma (MM).
METHODS
Tumor cell-specific phosphotyrosine-STAT3 (PY-STAT3) expression at the time of diagnosis was evaluated with dual immunohistochemical (IHC) staining for PY-STAT3 and CD138.
RESULTS
PY-STAT3 positivity was detected in 10 patients (10.6%), including three who showed strong expression. PY-STAT3-positive patients had higher serum C-reactive protein and calcium levels at diagnosis than did PY-STAT3-negative patients. PY-STAT3 positivity had predictive value for poor progression-free survival (PFS; P=0.001) and overall survival (OS; P=0.003). Among the 60 patients who received frontline autologous stem cell transplantation, PY-STAT3-positive patients had poorer PFS than did PY-STAT3-negative patients (4.2 vs. 19.2 mo, respectively; P=0.013). Multivariate analysis identified PY-STAT3 expression as an independent prognostic factor for PFS (relative risk [RR]=2.706, P=0.014) and OS (RR=3.091, P=0.044).
CONCLUSION
These data show that PY-STAT3 positivity, as determined using dual IHC, is a marker of poor prognosis in non-elderly adult patients with MM.

Keyword

STAT3; Multiple myeloma; Prognosis

MeSH Terms

Adult*
C-Reactive Protein
Calcium
Diagnosis
Disease-Free Survival
Humans
Multiple Myeloma*
Multivariate Analysis
Prognosis
STAT3 Transcription Factor
Stem Cell Transplantation
C-Reactive Protein
Calcium
STAT3 Transcription Factor

Figure

• 

  Fig. 1 Dual immunohistochemical staining of bone marrow sections obtained at diagnosis shows (A, B) plasma cells positive for CD138 (brown cell membranes) and negative for STAT3 expression and (C, D) plasma cells positive for both CD138 and STAT3 (red nuclei, ×400, ×1,000).

• 

  Fig. 2 Kaplan–Meier survival curves for progression-free survival and overall survival according to (A, B) PY-STAT3-positivity and (C, D) intensity of PY-STAT3 expression.

• 

  Fig. 3 Kaplan–Meier survival curves for (A) progression-free survival and (B) overall survival according to PY-STAT3 positivity in patients who underwent frontline autologous stem cell transplantation.

Reference

1. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet. 2009; 374:324–339. PMID: 19541364.

2. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008; 111:2516–2520. PMID: 17975015.

3. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014; 28:1122–1128. PMID: 24157580.

4. Bianchi G, Ghobrial IM. Biological and clinical implications of clonal heterogeneity and clonal evolution in multiple myeloma. Curr Cancer Ther Rev. 2014; 10:70–79. PMID: 25705146.

5. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005; 23:3412–3420. PMID: 15809451.

6. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014; 14:736–746. PMID: 25342631.

7. Lee H, Herrmann A, Deng JH, et al. Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell. 2009; 15:283–293. PMID: 19345327.

8. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009; 9:798–809. PMID: 19851315.

9. Darnell JE. Validating Stat3 in cancer therapy. Nat Med. 2005; 11:595–596. PMID: 15937466.

10. Nelson EA, Walker SR, Kepich A, et al. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood. 2008; 112:5095–5102. PMID: 18824601.

11. Kube D, Holtick U, Vockerodt M, et al. STAT3 is constitutively activated in Hodgkin cell lines. Blood. 2001; 98:762–770. PMID: 11468177.

12. Chiarle R, Simmons WJ, Cai H, et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat Med. 2005; 11:623–629. PMID: 15895073.

13. Huang X, Meng B, Iqbal J, et al. Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2013; 31:4520–4528. PMID: 24220563.

14. Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999; 10:105–115. PMID: 10023775.

15. Bharti AC, Shishodia S, Reuben JM, et al. Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis. Blood. 2004; 103:3175–3184. PMID: 15070700.

16. Monaghan KA, Khong T, Burns CJ, Spencer A. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia. 2011; 25:1891–1899. PMID: 21788946.

17. Scuto A, Krejci P, Popplewell L, et al. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia. 2011; 25:538–550. PMID: 21164517.

18. Brown R, Yang S, Weatherburn C, et al. Phospho-flow detection of constitutive and cytokine-induced pSTAT3/5, pAKT and pERK expression highlights novel prognostic biomarkers for patients with multiple myeloma. Leukemia. 2015; 29:483–490. PMID: 24990616.

19. Xiong H, Du W, Wang JL, et al. Constitutive activation of STAT3 is predictive of poor prognosis in human gastric cancer. J Mol Med (Berl). 2012; 90:1037–1046. PMID: 22328012.

20. Yang C, Lee H, Jove V, et al. Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS One. 2013; 8:e54029. PMID: 23326565.

21. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008; 454:436–444. PMID: 18650914.

22. Kujawski M, Kortylewski M, Lee H, Herrmann A, Kay H, Yu H. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest. 2008; 118:3367–3377. PMID: 18776941.

23. Grivennikov S, Karin E, Terzic J, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009; 15:103–113. PMID: 19185845.

24. Offidani M, Corvatta L, Polloni C, et al. Serum C-reactive protein at diagnosis and response to therapy is the most powerful factor predicting outcome of multiple myeloma treated with thalidomide/ anthracycline-based therapy. Clin Lymphoma Myeloma. 2008; 8:294–299. PMID: 18854284.

25. Tienhaara A, Pulkki K, Mattila K, Irjala K, Pelliniemi TT. Serum immunoreactive interleukin-6 and C-reactive protein levels in patients with multiple myeloma at diagnosis. Br J Haematol. 1994; 86:391–393. PMID: 8199033.

26. Ege H, Gertz MA, Markovic SN, et al. Prediction of survival using absolute lymphocyte count for newly diagnosed patients with multiple myeloma: a retrospective study. Br J Haematol. 2008; 141:792–798. PMID: 18410454.

27. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996; 335:91–97. PMID: 8649495.

28. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003; 348:1875–1883. PMID: 12736280.

29. Koreth J, Cutler CS, Djulbegovic B, et al. High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant. 2007; 13:183–196. PMID: 17241924.

30. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014; 371:895–905. PMID: 25184862.