Normal B-cell homeostasis requires a balance between survival and apoptotic signals. In B-CLL, where dysregulation of the apoptotic machinery imparts advantages towards clonal expansion and chemoresistance, CD40 is instrumental in modulating expression of Fas and other apoptosis-regulatory genes. We have found that while CD40L induces a striking upregulation of Fas (CD95) in B-CLL cells, it also upregulates the Fas-inhibitor cFLIP and increases cellular resistance to Fas-induced apoptosis. Goals of this project are to: l) compare CD40-mediated induction of Fas and cFLIP in normal B- lymphocytes and B-CLL cells to determine if cFLIP upregulation is normal or abnormal in Fas-stimulated B cells; 2) explore whether CD40 regulates Fas and cFLIP expression through transcriptional mechanisms and identify the responsible CD40-activated transcription factor(s); 3) delineate the CD40 signal transduction mechanisms responsible for induction of Fas and cFLIP, making correlations with TRAF binding and/or kinase recruitment; and 4) determine whether ablation of cFLIP expression sensitizes B-CLL cells to Fas-induced apoptosis. Dissecting CD40 control of Fas and cFLIP gene regulation allows for intervention, where selective cFLIP inhibition can re-sensitize B-CLL towards apoptosis without compromising Fas expression, thereby ensuring immune-mediated elimination of B-CLL cells.
| Chan, Henry; Reed, John C (2005) TRAF-dependent association of protein kinase Tpl2/COT1 (MAP3K8) with CD40. Biochem Biophys Res Commun 328:198-205 |
