Constitutive NF-kappaB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival.
Abnormalities in B-lymphocyte CD40 ligand (CD154) expression have been described for a number of immunologic diseases, including B-cell lymphomas. Although functional analysis of the CD154 gene and protein has been extensive, little is known about the mechanisms controlling CD154 expression in activated T cells, and even less is known for normal and malignant B cells. In this study we describe the transcriptional mechanism controlling CD154 expression in large B-cell lymphoma (LBCL). We show that the nuclear factor of activated T cells (NFAT) transcription factor is also constitutively activated in LBCL. We demonstrate that the constitutively active NFATc1 and c-rel members of the NFAT and nuclear factor-kappaB (NF-kappaB) families of transcription factors, respectively, directly interact with each other, bind to the CD154 promoter, and synergistically activate CD154 gene transcription. Down-regulation of NFATc1 or c-rel with small interfering RNA (siRNA) or chemical inhibitors inhibits CD154 gene transcription and lymphoma cell growth. These findings suggest that targeting NF-kappaB and NFAT, by inhibiting the expression of these transcription factors, or interdicting their interaction may provide a therapeutic rationale for patients with non-Hodgkin lymphoma of B-cell origin, and possibly other disorders that display dysregulated CD154 expression.
Pham
Lan V
LV
Department of Hematopathology, Box 54, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Tamayo
Archito T
AT
Yoshimura
Linda C
LC
Lin-Lee
Yen-Chiu
YC
Ford
Richard J
RJ
D023201:CD40 Ligand / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D016393:Lymphoma, B-Cell / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D016328:NF-kappa B; D050778:NFATC Transcription Factors; D023201:CD40 Ligand