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http://dx.doi.org/10.3904/kjim.2014.29.6.785

Clinical significance of nuclear factor ${\kappa}B$ and chemokine receptor CXCR4 expression in patients with diffuse large B-cell lymphoma who received rituximab-based therapy  

Shin, Ho Cheol (Department of Hematology and Oncology, Kyungpook National University Hospital)
Seo, Jongwon (Department of Hematology and Oncology, Kyungpook National University Hospital)
Kang, Byung Woog (Department of Hematology and Oncology, Kyungpook National University Hospital)
Moon, Joon Ho (Department of Hematology and Oncology, Kyungpook National University Hospital)
Chae, Yee Soo (Department of Hematology and Oncology, Kyungpook National University Hospital)
Lee, Soo Jung (Department of Hematology and Oncology, Kyungpook National University Hospital)
Lee, Yoo Jin (Department of Hematology and Oncology, Kyungpook National University Hospital)
Han, Seoae (Department of Hematology and Oncology, Kyungpook National University Hospital)
Seo, Sang Kyung (Department of Hematology and Oncology, Kyungpook National University Hospital)
Kim, Jong Gwang (Department of Hematology and Oncology, Kyungpook National University Hospital)
Sohn, Sang Kyun (Department of Hematology and Oncology, Kyungpook National University Hospital)
Park, Tae-In (Department of Pathology, Kyungpook National University Hospital)
Publication Information
The Korean journal of internal medicine / v.29, no.6, 2014 , pp. 785-792 More about this Journal
Abstract
Background/Aims: This study investigated the expression of nuclear factor ${\kappa}B$ (NF-${\kappa}B$) and the chemokine receptor (CXCR4) in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based therapy. Methods: Seventy patients with DLBCL and treated with rituximab-CHOP (R-CHOP) were included, and immunohistochemistry was performed to determine the expression of NF-${\kappa}B$ ($I{\kappa}B$ kinase ${\alpha}$, p50, and p100/p52) and CXCR4. To classify DLBCL cases as germinal center B-cell-like (GCB) and non-GCB, additional immunohistochemical expression of CD10, bcl-6, or MUM1 was used in this study. The expression was divided into two groups according to the intensity score (negative, 0 or 1+; positive, 2+ or 3+). Results: The median age of the patients was 66 years (range, 17 to 87), and 58.6% were male. Twenty-seven patients (38.6%) had stage III or IV disease at diagnosis. Twenty-three patients (32.9%) were categorized as high or high-intermediate risk according to their International Prognostic Indexs (IPIs). The overall incidence of bone marrow involvement was 5.7%. Rates of positive NF-${\kappa}B$ and CXCR4 expression were 84.2% and 88.6%, respectively. High NF-${\kappa}B$ expression was associated with CXCR4 expression (p = 0.002), and 56 patients (80.0%) showed coexpression. However, the expression of NF-${\kappa}B$ or CXCR4 was not associated with overall survival and EFS. On multivariate analysis that included age, gender, performance status, stage, and the IPI, no significant association between the grade of NF-${\kappa}B$ or CXCR4 expression and survival was observed. Conclusions: The current study suggests that the tissue expression of NF-${\kappa}B$ and CXCR4 may not be an independent prognostic marker in DLBCL patients treated with R-CHOP.
Keywords
Lymphoma; NF-kappa B; CXCR4;
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1 Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242.   DOI   ScienceOn
2 Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004;103:275-282.   DOI   ScienceOn
3 Scupoli MT, Donadelli M, Cioffi F, et al. Bone marrow stromal cells and the upregulation of interleukin-8 production in human T-cell acute lymphoblastic leukemia through the CXCL12/CXCR4 axis and the NF-kappaB and JNK/AP-1 pathways. Haematologica 2008;93:524-532.   DOI   ScienceOn
4 The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993;329:987-994.   DOI   ScienceOn
5 Armitage JO. Staging non-Hodgkin lymphoma. CA Cancer J Clin 2005;55:368-376.   DOI   ScienceOn
6 Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586.   DOI   ScienceOn
7 Nogai H, Dorken B, Lenz G. Pathogenesis of non-Hodgkin's lymphoma. J Clin Oncol 2011;29:1803-1811.   DOI   ScienceOn
8 Espinosa I, Briones J, Bordes R, et al. Activation of the NF-kappaB signalling pathway in diffuse large B-cell lymphoma: clinical implications. Histopathology 2008;53:441-449.   DOI   ScienceOn
9 Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001;194:1861-1874.   DOI
10 Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 2009;459:717-721.   DOI   ScienceOn
11 Saito B, Shiozawa E, Usui T, et al. Rituximab with chemotherapy improves survival of non-germinal center type untreated diffuse large B-cell lymphoma. Leukemia 2007;21:2563-2566.   DOI   ScienceOn
12 Ahn JY, Seo K, Weinberg OK, Arber DA. The prognostic value of CXCR4 in acute myeloid leukemia. Appl Immunohistochem Mol Morphol 2013;21:79-84.
13 Yao X, Zhou L, Han S, Chen Y. High expression of CXCR4 and CXCR7 predicts poor survival in gallbladder cancer. J Int Med Res 2011;39:1253-1264.   DOI
14 Jazirehi AR, Huerta-Yepez S, Cheng G, Bonavida B. Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-{kappa}B signaling pathway in non-Hodgkin's lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Res 2005;65:264-276.
15 Kwak JY. Treatment of diffuse large B cell lymphoma. Korean J Intern Med 2012;27:369-377.   DOI   ScienceOn
16 Pavan A, Spina M, Canzonieri V, Sansonno S, Toffoli G, De Re V. Recent prognostic factors in diffuse large B-cell lymphoma indicate NF-kappaB pathway as a target for new therapeutic strategies. Leuk Lymphoma 2008;49:2048-2058.   DOI   ScienceOn
17 Johnson PW. New targets for lymphoma treatment. Ann Oncol 2008;19 Suppl 4:iv56-iv59.
18 Jost PJ, Ruland J. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 2007;109:2700-2707.
19 Bavi P, Uddin S, Bu R, et al. The biological and clinical impact of inhibition of NF-kappaB-initiated apoptosis in diffuse large B cell lymphoma (DLBCL). J Pathol 2011;224:355-366.   DOI   ScienceOn
20 Calandra G, Bridger G, Fricker S. CXCR4 in clinical hematology. Curr Top Microbiol Immunol 2010;341:173-191.
21 Bertolini F, Dell'Agnola C, Mancuso P, et al. CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin's lymphoma. Cancer Res 2002;62:3106-3112.
22 Okera M, Bae K, Bernstein E, et al. Evaluation of nuclear factor kappaB and chemokine receptor CXCR4 co-expression in patients with prostate cancer in the Radiation Therapy Oncology Group (RTOG) 8610. BJU Int 2011;108(2 Pt 2):E51-E58.   DOI   ScienceOn
23 Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P, et al. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 2003;278:21631-21638.   DOI   ScienceOn
24 Jung SJ, Kim CI, Park CH, et al. Correlation between chemokine receptor CXCR4 expression and prognostic factors in patients with prostate cancer. Korean J Urol 2011;52:607-611.   DOI   ScienceOn
25 Sekiya R, Kajiyama H, Sakai K, et al. Expression of CXCR4 indicates poor prognosis in patients with clear cell carcinoma of the ovary. Hum Pathol 2012;43:904-910.   DOI   ScienceOn