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

Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B-cell lymphoma

  1. Hai-Jun Zhou1,
  2. Lan V. Pham1,
  3. Archito T. Tamayo1,
  4. Yen-Chiu Lin-Lee1,
  5. Lingchen Fu1,
  6. Linda C. Yoshimura1, and
  7. Richard J. Ford1
  1. 1Department of Hematopathology, the University of Texas M. D. Anderson Cancer Center, Houston

Abstract

CD40 is an integral plasma membrane–associated member of the TNF receptor family that has recently been shown to also reside in the nucleus of both normal B cells and large B-cell lymphoma (LBCL) cells. However, the physiological function of CD40 in the B-cell nucleus has not been examined. In this study, we demonstrate that nuclear CD40 interacts with the NF-κB protein c-Rel, but not p65, in LBCL cells. Nuclear CD40 forms complexes with c-Rel on the promoters of NF-κB target genes, CD154, BLyS/BAFF, and Bfl-1/A1, in various LBCL cell lines. Wild-type CD40, but not NLS-mutated CD40, further enhances c-Rel–mediated Blys promoter activation as well as proliferation in LBCL cells. Studies in normal B cells and LBCL patient cells further support a nuclear transcriptional function for CD40 and c-Rel. Cooperation between nuclear CD40 and c-Rel appears to be important in regulating cell growth and survival genes involved in lymphoma cell proliferation and survival mechanisms. Modulating the nuclear function of CD40 and c-Rel could reveal new mechanisms in LBCL pathophysiology and provide potential new targets for lymphoma therapy.

  • Submitted February 8, 2006.
  • Accepted June 9, 2007.
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