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Research Paper|Volume 8, Issue 12|pp 3321—3340

RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma

Mingzhi Zhang1,2, Zijun Y. Xu-Monette2, Ling Li1, Ganiraju C. Manyam3, Carlo Visco4, Alexandar Tzankov5, Jing Wang3, Santiago Montes-Moreno6, Karen Dybkaer7, April Chiu8, Attilio Orazi9, Youli Zu10, Govind Bhagat11, Kristy L. Richards12, Eric D. Hsi13, William W.L. Choi14, J. Han van Krieken15, Jooryung Huh16, Maurilio Ponzoni17, Andrés J.M. Ferreri17, Michael B. Møller18, Ben M. Parsons19, Jane N. Winter20, Miguel A. Piris6, L. Jeffrey Medeiros2, Lan V. Pham2, Ken H. Young2,21
  • 1Department of Oncology, The First Affiliated Hospital Zhengzhou University, Zhengzhou, Henan, China
  • 2Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
  • 3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
  • 4San Bortolo Hospital, Vicenza, Italy
  • 5University Hospital, Basel, Switzerland
  • 6Hospital Universitario Marques de Valdecilla, Santander, Spain
  • 7Aalborg University Hospital, Aalborg, Denmark
  • 8Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
  • 9Weill Medical College of Cornell University, New York, NY 10065, USA
  • 10The Methodist Hospital, Houston, TX 77030, USA
  • 11Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032, USA
  • 12University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA
  • 13Cleveland Clinic, Cleveland, OH 44195, USA
  • 14University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China
  • 15Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
  • 16Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea
  • 17San Raffaele H. Scientific Institute, Milan, Italy
  • 18Odense University Hospital, Odense, Denmark
  • 19Gundersen Medical Foundation, La Crosse, WI 54601, USA
  • 20Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
  • 21The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, TX 77030, USA

* * Equal contribution

Received: October 29, 2016Accepted: November 11, 2016Published: December 8, 2016

Abstract

It has been well established that nuclear factor kappa-B (NF-κB) activation is important for tumor cell growth and survival. RelA/p65 and p50 are the most common NF-kB subunits and involved in the classical NF-kB pathway. However, the prognostic and biological significance of RelA/p65 is equivocal in the field. In this study, we assessed RelA/p65 nuclear expression by immunohistochemistry in 487 patients with de novo diffuse large B-cell lymphoma (DLBCL), and studied the effects of molecular and pharmacological inhibition of NF-kB on cell viability. We found RelA/p65 nuclear expression, without associations with other apparent genetic or phenotypic abnormalities, had unfavorable prognostic impact in patients with stage I/II DLBCL. Gene expression profiling analysis suggested immune dysregulation and antiapoptosis may be relevant for the poorer prognosis associated with p65 hyperactivation in germinal center B-cell–like (GCB) DLBCL and in activated B-cell–like (ABC) DLBCL, respectively. We knocked down individual NF-κB subunits in representative DLBCL cells in vitro, and found targeting p65 was more effective than targeting other NF-κB subunits in inhibiting cell growth and survival. In summary, RelA/p65 nuclear overexpression correlates with significant poor survival in early-stage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-κB hyperactivation.