Blood Journal
Leading the way in experimental and clinical research in hematology

Constitutive NF-κB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival

  1. Lan V. Pham,
  2. Archito T. Tamayo,
  3. Linda C. Yoshimura,
  4. Yen-Chiu Lin-Lee, and
  5. Richard J. Ford
  1. From the Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, and the Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, TX.

Abstract

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–κB (NF-κB) 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-κB 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.

  • Submitted March 22, 2005.
  • Accepted August 2, 2005.
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