The Journal of Experimental Medicine
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Published 17 December 2001. doi:10.1084/jem.194.12.1861
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© Rockefeller University Press, 0022-1007/2001/12/1861/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 12, December 17, 2001 1861-1874

Original Article

 Constitutive Nuclear Factor {kappa}B Activity Is Required for Survival of Activated B Cell–like Diffuse Large B Cell Lymphoma Cells

R. Eric Davis1, Keith D. Brown2, Ulrich Siebenlist2 and Louis M. Staudt1

1 Metabolism Branch, Center for Cancer Research, National Cancer Institute
2 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Louis M. Staudt, Metabolism Branch, CCR, NCI Bldg. 10, Rm. 4N114 NIH, 9000 Rockville Pike, Bethesda, MD 20892-1374. Phone: 301-402-1892; Fax: 301-496-9956; E-mail: lstaudt{at}mail.nih.gov

Gene expression profiling has revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two distinct diseases. Patients with one DLBCL subtype, termed activated B cell–like (ABC) DLBCL, have a distinctly inferior prognosis. An untapped potential of gene expression profiling is its ability to identify pathogenic signaling pathways in cancer that are amenable to therapeutic attack. The gene expression profiles of ABC DLBCLs were notable for the high expression of target genes of the nuclear factor (NF)-{kappa}B transcription factors, raising the possibility that constitutive activity of the NF-{kappa}B pathway may contribute to the poor prognosis of these patients. Two cell line models of ABC DLBCL had high nuclear NF-{kappa}B DNA binding activity, constitutive I{kappa}B kinase (IKK) activity, and rapid I{kappa}B{alpha} degradation that was not seen in cell lines representing the other DLBCL subtype, germinal center B-like (GCB) DLBCL. Retroviral transduction of a super-repressor form of I{kappa}B{alpha} or dominant negative forms of IKKß was toxic to ABC DLBCL cells but not GCB DLBCL cells. DNA content analysis showed that NF-{kappa}B inhibition caused both cell death and G1-phase growth arrest. These findings establish the NF-{kappa}B pathway as a new molecular target for drug development in the most clinically intractable subtype of DLBCL and demonstrate that the two DLBCL subtypes defined by gene expression profiling utilize distinct pathogenetic mechanisms.

Key Words: gene expression profiling • signal transduction • I{kappa}B kinase • microarray • apoptosis


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