The biological and clinical impact of inhibition of NF- ĸB initiated apoptosis in diffuse large B-cell lymphoma (DLBCL)

Authors

Prashant Bavi, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia
Shahabuddin, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia
Rong Bu, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia
Maqbool Ahmed, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia
Jehad Abubaker, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia
Valorie Balde, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia
Zeeshan Qadri, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia
Dahish Ajarim, King Faisal Cancer Centre, Riyadh, Saudi Arabia
Fouad Al-Dayel, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Azhar Hussain, Aga Khan UniversityFollow
Khawla S Al-Kuraya, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia

Document Type

Article

Department

Centre for Regenerative Medicine

Abstract

NF-κB is frequently over-expressed in a variety of non-Hodgkin's lymphomas (NHLs) and has been implicated in lymphomagenesis; however, its role in diffuse large B cell lymphoma (DLBCL) as a prognostic biomarker has not been fully elucidated. Therefore, we investigated the role of NF-κB and its association with clinicopathological features in a tissue microarray cohort of 230 DLBCL patient samples. We then elucidated the role of NF-κB inhibition on cell viability and apoptosis in vitro, using DLBCL cell lines. Using immunohistochemistry, NF-κB was detected in 25.6% (52/203) DLBCL tumours, was associated with activated B cell (ABC) phenotype (p = 0.0054), Epstein–Barr virus (EBV; p = 0.0080) and over-expression of the anti-apoptotic marker XIAP (p = 0.0013). DLBCL cases with nuclear expression of NF-κB showed a significantly poorer overall survival as compared to those without NF-κB expression (p = 0.0236). In a multivariate analysis using a Cox proportional hazard model for IPI and NF-κB expression, the relative risk was 2.97 for high NF-κB expression (95% CI 1.27–6.94; p = 0.0113) and 7.55 for the high-IPI group (95% CI 3.34–18.35; p < 0.0001). In vitro, Bay 11-7085 inhibited constitutively active NF-κB expression in a dose-dependent manner and inhibition of NF-κB also down-regulated expression of the downstream target gene products Bcl-2, Bcl-XL (BCL2L1), XIAP and Survivin, leading to apoptosis via activation of the mitochondrial apoptotic pathway. NF-κB over-expression was found to be an independent prognostic marker for poor survival in DLBCL. Altogether, these results suggest that NF-κB may be a useful prognostic biomarker and a potential target for therapeutic intervention in DLBCL. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Comments

This work was published before the author joined Aga Khan University.

Publication (Name of Journal)

The Journal of Pathology

Recommended Citation

Bavi, P., Shahabuddin, ., Bu, R., Ahmed, M., Abubaker, J., Balde, V., Qadri, Z., Ajarim, D., Al-Dayel, F., Hussain, A., Al-Kuraya, K. (2011). The biological and clinical impact of inhibition of NF- ĸB initiated apoptosis in diffuse large B-cell lymphoma (DLBCL). The Journal of Pathology, 224(3), 355-366.
Available at: https://ecommons.aku.edu/crm/20