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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2121-2127.
Prepublished online as a Blood First Edition Paper on June 13, 2007; DOI 10.1182/blood-2007-02-073080.
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Submitted February 8, 2007
Accepted June 9, 2007
Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B cell Lymphoma
Hai-Jun Zhou, Lan V. Pham, Archito T. Tamayo, Yen-Chiu Lin-Lee, Lingchen Fu, Linda C. Yoshimura, and Richard J. Ford*
Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: rford{at}mdanderson.org.
CD40 is an integral plasma membrane-associated member of the TNF receptor family that has been recently 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- B protein-c-Rel, but not p65, in LBCL cells. Nuclear CD40 forms complexes with c-Rel on the promoters of NF-B 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.
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