Analysis of NF-κB Pathway Proteins in Pediatric Hodgkin Lymphoma: Correlations with EBV Status and Clinical Outcome-A Children's Oncology Group Study.

Terzah M Horton,Sonia Narendra,Meng-Fen Wu,Hao Liu,Dolores López-Terrada,Andrea M Sheehan,Robert E Hutchison

doi:10.1155/2012/341629

Abstract

Constitutively active nuclear factor-κB (NF-κB) is integral to the survival of Hodgkin/Reed-Sternberg cells (H/RS) in Hodgkin Lymphoma (HL). To investigate NF-κB pathway proteins in pediatric HL, we utilized a tissue microarray compiled from 102 children enrolled in the Children's Oncology Group intermediate-risk clinical trial AHOD0031 (56 male, 78 Caucasian, median age 15y (range 1-20y), 85 nodular sclerosing subtype, 23 Epstein Barr virus (EBV) positive, 24 refractory/relapsed disease). We examined the intensity, localization, and pathway correlations of NF-κB pathway proteins (Rel-A/p65, Rel-B, c-Rel, NF-κB1, NF-κB2, IκB-α, IKK-α, IKK-β, IKK-γ/NEMO, NIK, A20), as well as their associations with EBV status and clinical outcome. NF-κB pathway proteins were overexpressed in pediatric HL patients compared to controls. Patients with EBV-tumors, or with rapid early therapy response, had tightly coordinated regulation of NF-κB pathway proteins, whereas patients with EBV+ tumors, or slow early therapy response, had little coordinated NF-κB pathway regulation. High NIK expression was associated with a slow response to therapy and decreased EFS. Elevated Rel-B, NIK and the NF-κB inhibitor A20 were associated with decreased EFS in multivariate analysis. These studies suggest a pivotal role for the NF-κB pathway in therapy response and patient survival (clinicaltrials.gov identifier: ).

Highlights

Constitutive activation of nuclear factor-κB (NF-κB) is one of the hallmarks of Hodgkin/Reed-Sternberg cells (H/RS) cells in Hodgkin lymphoma (HL) [1]
The demographics of pediatric HL patients included on the array were similar to those observed in the AHOD0031 clinical trial with respect to age, sex, race, histology, EBV status, and response to therapy (Table 1)
We report a comprehensive study of NF-κB pathway activation in pediatric HL patients using Tissue microarrays (TMA)

Summary

Introduction

Constitutive activation of NF-κB is one of the hallmarks of H/RS cells in HL [1]. NF-κB is a transcription factor family composed of five members: Rel-A/p65, Rel-B, c-Rel, NK-κB1 (p50/p105), and NF-κB2 (p52/p100) [2]. NF-κB subunits Rel-A and c-rel are sequestered in the cytoplasm by IκB. In the classical pathway (Figure 1(a)), an IκB-kinase (IKK). Complex regulates IκB and the release of Rel-A and c-rel into the nucleus. NF-κB is activated by proteasomal cleavage of NF-κB2 (p100) to p52, an NFκB subunit that binds and activates Rel-B (Figure 1(b)) [3]. NF-κB subunits dimerize and translocate into the nucleus, where they activate transcription of NFκB target genes [4,5,6]. Both the classical and alternative NFκB pathways are tightly regulated.

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Results

Conclusion