RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma.
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.
Duke Scholars
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Related Subject Headings
- Transcription Factor RelA
- Signal Transduction
- NF-kappa B
- Middle Aged
- Male
- Lymphoma, Large B-Cell, Diffuse
- Humans
- Gene Expression Regulation, Neoplastic
- Gene Expression Profiling
- Female
Citation
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Transcription Factor RelA
- Signal Transduction
- NF-kappa B
- Middle Aged
- Male
- Lymphoma, Large B-Cell, Diffuse
- Humans
- Gene Expression Regulation, Neoplastic
- Gene Expression Profiling
- Female