%0 Journal Article
%T Analysis of NF- B Pathway Proteins in Pediatric Hodgkin Lymphoma: Correlations with EBV Status and Clinical Outcome¡ªA Children's Oncology Group Study
%A Terzah M. Horton
%A Andrea M. Sheehan
%A Dolores L¨®pez-Terrada
%A Robert E. Hutchison
%A Sonia Narendra
%A Meng-Fen Wu
%A Hao Liu
%J Lymphoma
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/341629
%X Constitutively active nuclear factor- B (NF- B) is integral to the survival of Hodgkin/Reed-Sternberg cells (H/RS) in Hodgkin lymphoma (HL). To investigate NF- B 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 15 years (range 1¨C20 years), 85 nodular sclerosing subtype, 23 Epstein-Barr virus (EBV) positive, and 24 refractory/relapsed disease). We examined the intensity, localization, and pathway correlations of NF- B pathway proteins (Rel-A/p65, Rel-B, c-Rel, NF- B1, NF- B2, I B- , IKK- , IKK- , IKK- /NEMO, NIK, and A20), as well as their associations with EBV status and clinical outcome. NF- B 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- B pathway proteins, whereas patients with EBV+ tumors, or slow early therapy response, had little coordinated NF- B pathway regulation. High NIK expression was associated with a slow response to therapy and decreased EFS. Elevated Rel-B, NIK, and the NF- B inhibitor A20 were associated with decreased EFS in multivariate analysis. These studies suggest a pivotal role for the NF- B pathway in therapy response and patient survival in Hodgkin lymphoma. 1. Introduction Constitutive activation of NF- B is one of the hallmarks of H/RS cells in HL [1]. NF- B is a transcription factor family composed of five members: Rel-A/p65, Rel-B, c-Rel, NK- B1 (p50/p105), and NF- B2 (p52/p100) [2]. NF- B subunits Rel-A and c-rel are sequestered in the cytoplasm by I B. In the classical pathway (Figure 1(a)), an I B-kinase (IKK) complex regulates I B and the release of Rel-A and c-rel into the nucleus. In the alternative pathway, NF- B is activated by proteasomal cleavage of NF- B2 (p100) to p52, an NF- B subunit that binds and activates Rel-B (Figure 1(b)) [3]. Once activated, NF- B subunits dimerize and translocate into the nucleus, where they activate transcription of NF- B target genes [4¨C6]. Both the classical and alternative NF- B pathways are tightly regulated. In the classical pathway, degradation of I B- and I B- is triggered by IKK- activation. In the alternative pathway, IKK- is tightly regulated by NF- B inducing kinase (NIK). IKKs are negatively regulated by A20, an E3 ligase/deubiquitinase, and putative tumor suppressor in HL. Figure 1: Classical and alternative NF- B pathway activation. (a) Activation of the classical NF- B
%U http://www.hindawi.com/journals/lymph/2012/341629/