ELEVATED LEVELS OF BIOLOGICALLY-ACTIVE SOLUBLE CD40 LIGAND IN THE SERUM OF PATIENTS WITH CHRONIC LYMPHOCYTIC-LEUKEMIA

Chronic lymphocytic leukaemia (CLL) is an indolent lymphoproliferative disorder manifested by low growth fraction and prolonged survival of the malignant cells, The mechanisms that enable CLL cells to live long er and to resist apoptosis remain unclear. Because the malignant CLL c ells express CD40 and Fas receptors, which can transduce cell-survival and cell-death signals, we examined the role of CD40 in the growth re gulation of CLL cells and its interaction with Fas-mediated and fludar abine-induced apoptosis in vitro. Primary CLL cells underwent spontane ous apoptosis in culture, which was enhanced by exogenous human Fas li gand (FasL) or fludarabine. Exogenous CD40L rescued CLL cells from spo ntaneous apoptosis in a dose-dependent manner, and caused CLL cells to resist apoptosis induced by FasL or fludarabine. Patients' autologous plasma rescued CLL cells from spontaneous apoptosis, an effect that c ould be reversed with anti-CD40 ligand (CD40L) antibodies. The levels of soluble CD40 ligand in the sera of 51 CLL patients and 55 healthy d onors were determined by enzyme-linked immunosorbent assay. The mean s oluble CD40L level in normal donors was 0.29 ng/ml compared to a mean value of 0.80 ng/ml in CLL patients (P<0.001). CD40L up-regulated bcl- X-L mRNA but not bcl-2 in CLL cells within 3-6 h in culture. Our resul ts demonstrated that serum of patients with CLL contained elevated lev els of biologically active soluble CD40L, and that CD40L can prolong s urvival of CLL cells and mediate their resistance to Fast and fludarab ine in vitro.