Yıl: 2019 Cilt: 44 Sayı: 4 Sayfa Aralığı: 499 - 509 Metin Dili: İngilizce DOI: 10.1515/tjb-2018-0321 İndeks Tarihi: 06-06-2020

Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia

Öz:
Objectives: Rituximab is a monoclonal antibody that targets the B-lymphocyte surface antigen CD20. It is used in the treatment of some diseases including B-cell chroniclymphocytic leukemia (B-CLL). There are a lot of data regarding effect of Rituximab on lymphoma cells. But, there is no satisfactory information about the effect ofRituximab on the signaling pathways in leukemia cells. In this study, it was aimed to understand the effect of Rituximab on JAK-STAT and NF-κB signaling pathways in B-cellacute lymphoblastic leukemia (B-ALL) and B-CLL.Material and methods: Apoptotic effect of Rituximab in the TANOUE (B-ALL) and EHEB (B-CLL) cell lines were evaluated by using the Annexin V method. mRNA expression levels of STAT3 and RelA were analysed by quantitative RT-PCR (Q-PCR). Alterations in STAT3 and RelA protein expressions were detected by using a chromogenicalkaline phosphatase assay after Western Blotting. Results: Rituximab had no apoptotic effect on both cell lines. Complement-mediated cytotoxicity was only detected in EHEB cells. mRNA and protein expressions ofSTAT3 and RelA genes were decreased following Rituximab treatment.Conclusion: Our preliminary results suggest that the use of Rituximab might be effective in B-ALL though bothsignaling pathways.
Anahtar Kelime:

Rituximab’ın akut lenfoblastik lösemi ve kronik lenfositik lösemide JAK-STAT ve NF-κB sinyal yolaklarına etkileri

Öz:
Amaç: Rituximab, B-lenfosit yüzey antijeni CD20’yi hedefleyen bir monoklonal antikordur. B-hücre kronik lenfositik lösemi (B-KLL) gibi bazı hastalıkların tedavisinde kullanılmaktadır. Rituximab’ın lenfoma hücrelerindeki etkisi ile ilgili birçok veri vardır. Ancak, lösemi hücrelerindeki sinyal yolaklarına etkisi ile ilgili yeterli bilgi bulunmamaktadır. Bu çalışmada, Rituximab’ ın, B-hücre akut lenfoblastik lösemi (B-ALL) ve B-KLL’deki JAK-STAT ve NF-κB sinyal yolakları üzerindeki etkisinin anlaşılması hedeflenmiştir. Gereç ve Yöntem: Rituximab’ ın TANOUE (B-ALL) ve EHEB (B-KLL) hücre hatlarındaki apoptotik etkisi Annexin V yöntemi ile belirlendi. STAT3 ve RelA’nın mRNA ekspresyon seviyeleri kantitatif RT-PCR (Q-PCR) ile analiz edildi. STAT3 ve RelA protein ekspresyonlarındaki değişimler Western Blot sonrası kromojenik alkalen fosfataz analizi ile tespit edildi. Bulgular: Rituximab’ın her iki hücre hattında apoptotik etkisi bulunmamaktadır. Kompleman-aracılı sitotoksisite sadece EHEB hücre hattında saptanmıştır. Rituximab uygulaması sonrası STAT3 ve RelA’nın mRNA ve protein ekspresyonları azalmıştır. Sonuç: İlk sonuçlarımız, Rituximab kullanımının B-ALL’ de her iki sinyal yolağı aracılığıyla etkili olabileceğini düşündürmektedir.
Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
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  • 1. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukemia. Lancet 2008;371:1030–43.
  • 2. Graux C. Biology of acute lymphoblastic leukemia (ALL): clinical and therapeutic relevance. Transfus Apher Sci 2011;44:183–9.
  • 3. Zuckerman T, Rowe JM. Pathogenesis and prognostication in acute lymphoblastic leukemia. F1000Prime Rep 2014;6:59.
  • 4. Ghia P, Ferreri AM, Caligaris-Cappio F. Chronic lymphocytic leukemia. Crit Rev Oncol Hematol 2007;64:234–46.
  • 5. Tausch E, Mertens D, Stilgenbauer S. Advances in treating chronic lymphocytic leukemia. F1000Prime Rep 2014;6:65.
  • 6. Hallek M. Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. Am J Hematol 2015;90:446–60.
  • 7. Benekli M, Baumann H, Wetzler M. Targeting signal transducer and activator of transcription signaling pathway in leukemias. J Clin Oncol 2009;27:4422–32.
  • 8. Packham G. The role of NF-kappaB in lymphoid malignancies. Br J Haematol 2008;143:3–15.
  • 9. Benekli M, Baer MR, Baumann H, Wetzler M. Signal transducer and activator of transcription proteins in leukemias. Blood 2003;101:2940–54.
  • 10. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 2007;21:1396–408.
  • 11. Yang J, Stark GR. Roles of unphosphorylated STATs in signaling. Cell Res 2008;18:443–51.
  • 12. Jost PJ, Ruland J. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 2007;109:2700–7.
  • 13. Lindström TM, Bennett PR. The role of nuclear factor kappa B in human labour. Reproduction 2005;130:569–81.
  • 14. Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF- kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 2010;21:11–9.
  • 15. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009;9:798–809.
  • 16. Selewski DT, Shah GV, Mody RJ, Rajdev PA, Mukherji SK. Rituxi- mab (Rituxan). AJNR Am J Neuroradiol 2010;31:1178–80.
  • 17. James DF, Kipps TJ. Rituximab in chronic lymphocytic leukemia. Adv Ther 2011;28:534–54.
  • 18. Bezombes C, Fournie JJ, Laurent G. Direct effect of rituximab in B-cell-derived lymphoid neoplasias: mechanism, regulation, and perspectives. Mol Cancer Res 2011;9:1435–42.
  • 19. Tedeschi A, Vismara E, Ricci F, Morra E, Montillo M. The spectrum of use of rituximab in chronic lymphocytic leukemia. Onco Targets Ther 2010;3:227–46.
  • 20. Hoelzer D, Gökbuget N. Chemoimmunotherapy in acute lympho- blastic leukemia. Blood Rev 2012;26:25–32.
  • 21. Maury S, Chevret S, Thomas X, Heim D, Leguay T, Huguet F, et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med 2016;375:1044–53.
  • 22. Kantarjian H, Thomas D, Wayne AS, O’Brien S. Monoclonal antibody-based therapies: a new dawn in the treatment of acute lymphoblastic leukemia. J Clin Oncol 2012;30:3876–83.
  • 23. Borowitz MJ, Shuster J, Carroll AJ, Nash M, Look AT, Camitta B, et al. Prognostic significance of fluorescence intensity of surface marker expression in childhood B-precursor acute lympho- blastic leukemia. A Pediatric Oncology Group Study. Blood 1997;89:3960–6.
  • 24. Kamazani FM, Bahoush-Mehdiabadi G, Aghaeipour M, Vaeli S, Amirghofran Z. The expression and prognostic impact of CD95 death receptor and CD20, CD34 and CD44 differentiation mark- ers in pediatric acute lymphoblastic leukemia. Iran J Pediatr 2014;24:371–80.
  • 25. Berinstein NL, Grillo-Lopez AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 1998;9:995–1001.
  • 26. Alas S, Bonavida B. Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non- hodgkin’s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res 2001;61:5137–44.
  • 27. Dı Gaetano N, Xıao Y, Erba E, Bassan R, Rambaldi A, Golay J, et al. Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol 2001;114:800–9.
  • 28. Sieber S, Gdynia G, Roth W, Bonavida B, Efferth T. Combi- nation treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. Int J Oncol 2009;35:149–58.
  • 29. Koivula S, Valo E, Raunio A, Hautaniemi S, Leppa S. Rituximab regulates signaling pathways and alters gene expression associated with cell death and survival in diffuse large B-cell lymphoma. Oncol Rep 2011;25:1183–90.
  • 30. Cartron G, Watier H, Golay J, Solal-Celigny P. From the bench to the bedside: ways to improve rituximab efficacy. Blood 2004;104:2635–42.
  • 31. Alas S, Ng CP, Bonavida B. Rituximab modifies the cisplatin- mitochondrial signaling pathway, resulting in apoptosis in cisplatin-resistant non-Hodgkin’s lymphoma. Clin Cancer Res 2002;8:836–45.
  • 32. Jazirehi AR, Vega MI, Chatterjee D, Goodglick L, Bonavida B. Inhibition of the Raf–MEK1/2–ERK1/2 signaling path- way, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin’s lymphoma B cells by Rituximab. Cancer Res 2004;64:7117–26.
  • 33. Jazirehi AR, Huerta-Yepez S, Cheng G, Bonavida B. Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitu- tive nuclear factor-kappaB signaling pathway in non-Hodgkin’s lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Res 2005;65:264–76.
  • 34. Shi W, Han X, Yao J, Yang J, Shi Y. Combined effect of histone deacetylase inhibitor suberoylanilide hydroxamic acid and anti- CD20 monoclonal antibody rituximab on mantle cell lymphoma cells apoptosis. Leuk Res 2012;36:749–55.
  • 35. Vega MI, Huerta-Yepaz S, Garban H, Jazirehi A, Emmanouilides C, Bonavida B. Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance. Oncogene 2004;23:3530–40.
  • 36. Li X, Wang X, Zhang M, Li A, Sun Z, Yu Q. Quercetin potenti- ates the antitumor activity of rituximab in diffuse large B-cell lymphoma by inhibiting STAT3 pathway. Cell Biochem Biophys 2014;70:1357–62.
  • 37. Vega MI, Huerta-Yepaz S, Jazirehi AR, Garban H, Bonavida B. Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis. Oncogene 2005;24:8114–27.
  • 38. Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F, et al. Early results of a chemoimmunotherapy regimen of fludara- bine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005;23:4079–88.
  • 39. Pescovitz MD. Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant 2006;6(5 Pt 1):859–66.
  • 40. Müller C, Murawski N, Wiesen MH, Held G, Poeschel V, Zeynal- ova S, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood 2012;119:3276–84.
  • 41. Counsilman CE, Jol-van der Zijde CM, Stevens J, Cransberg K, Bredius RG, Sukhai RN. Pharmacokinetics of rituximab in a pedi- atric patient with therapy-resistant nephrotic syndrome. Pediatr Nephrol 2015;30:1367–70.
  • 42. Boyd AW, Wawryk SO, Burns GF, Fecondo JV. Intercellular adhesion molecule-1 (ICAM-1) has a central role in cell-cell contact-mediated immune mechanisms. Proc Natl Acad Sci USA 1988;85:3095–9.
  • 43. Christiansen I, Gidlöf C, Wallgren AC, Simonsson B, Tötterman TH. Serum levels of soluble intercellular adhesion molecule-1 are increased in chronic B-lymphocyte leukemia and cor- relate with clinical stage and prognostic markers. Blood 1994;84:3010–6.
  • 44. Terol MJ, Tormo M, Martinez-Climent JA, Marugan I, Benet I, Ferrandez A, et al. Soluble intercellular adhesion molecule-1 (s-ICAM-1/s-CD54) in diffuse large B-cell lymphoma: asso- ciation with clinical characteristics and outcome. Ann Oncol 2003;14:467–74.
  • 45. Rudnicka D, Oszmiana A, Finch DK, Strickland I, Schofield DJ, Lowe DC, et al. Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell–mediated antibody- dependent cellular cytotoxicity. Blood 2013;121:4694–702.
APA DALMIZRAK A, SELVİ GÜNEL N, KAYMAZ B, KOSOVA B, Sahin F, SAYDAM G (2019). Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. , 499 - 509. 10.1515/tjb-2018-0321
Chicago DALMIZRAK Ayşegül,SELVİ GÜNEL Nur,KAYMAZ Burçin TEZCANLI,KOSOVA Buket,Sahin Fahri,SAYDAM Güray Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. (2019): 499 - 509. 10.1515/tjb-2018-0321
MLA DALMIZRAK Ayşegül,SELVİ GÜNEL Nur,KAYMAZ Burçin TEZCANLI,KOSOVA Buket,Sahin Fahri,SAYDAM Güray Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. , 2019, ss.499 - 509. 10.1515/tjb-2018-0321
AMA DALMIZRAK A,SELVİ GÜNEL N,KAYMAZ B,KOSOVA B,Sahin F,SAYDAM G Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. . 2019; 499 - 509. 10.1515/tjb-2018-0321
Vancouver DALMIZRAK A,SELVİ GÜNEL N,KAYMAZ B,KOSOVA B,Sahin F,SAYDAM G Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. . 2019; 499 - 509. 10.1515/tjb-2018-0321
IEEE DALMIZRAK A,SELVİ GÜNEL N,KAYMAZ B,KOSOVA B,Sahin F,SAYDAM G "Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia." , ss.499 - 509, 2019. 10.1515/tjb-2018-0321
ISNAD DALMIZRAK, Ayşegül vd. "Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia". (2019), 499-509. https://doi.org/10.1515/tjb-2018-0321
APA DALMIZRAK A, SELVİ GÜNEL N, KAYMAZ B, KOSOVA B, Sahin F, SAYDAM G (2019). Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. Türk Biyokimya Dergisi, 44(4), 499 - 509. 10.1515/tjb-2018-0321
Chicago DALMIZRAK Ayşegül,SELVİ GÜNEL Nur,KAYMAZ Burçin TEZCANLI,KOSOVA Buket,Sahin Fahri,SAYDAM Güray Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. Türk Biyokimya Dergisi 44, no.4 (2019): 499 - 509. 10.1515/tjb-2018-0321
MLA DALMIZRAK Ayşegül,SELVİ GÜNEL Nur,KAYMAZ Burçin TEZCANLI,KOSOVA Buket,Sahin Fahri,SAYDAM Güray Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. Türk Biyokimya Dergisi, vol.44, no.4, 2019, ss.499 - 509. 10.1515/tjb-2018-0321
AMA DALMIZRAK A,SELVİ GÜNEL N,KAYMAZ B,KOSOVA B,Sahin F,SAYDAM G Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. Türk Biyokimya Dergisi. 2019; 44(4): 499 - 509. 10.1515/tjb-2018-0321
Vancouver DALMIZRAK A,SELVİ GÜNEL N,KAYMAZ B,KOSOVA B,Sahin F,SAYDAM G Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia. Türk Biyokimya Dergisi. 2019; 44(4): 499 - 509. 10.1515/tjb-2018-0321
IEEE DALMIZRAK A,SELVİ GÜNEL N,KAYMAZ B,KOSOVA B,Sahin F,SAYDAM G "Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia." Türk Biyokimya Dergisi, 44, ss.499 - 509, 2019. 10.1515/tjb-2018-0321
ISNAD DALMIZRAK, Ayşegül vd. "Effects of Rituximab on JAK-STAT and NF-κB signaling pathways in acute lymphoblastic leukemia and chronic lymphocytic leukemia". Türk Biyokimya Dergisi 44/4 (2019), 499-509. https://doi.org/10.1515/tjb-2018-0321