Regulation of growth, differentiation and survival of B-chronic lymphocytic leukemia cells

Abstract: Chronic lymphocytic leukemia of B cell type (B-CLL) is the most commonform of leukemia in the Western countries. The signals regulating theexpansion of the B-CLL clone in vivo is yet far from being fully understood. Inthis thesis the regulation of proliferation, differentiation and survival bycell-cell interactions, cytokines and thioredoxin (Trx) has been investigatedin B-CLL cells in vitro. IL-4-induced homotypic adhesion did not influence theTPA-induced proliferation and differentiation of B-CLL cells. B-CLL cellswere found to differ from normal B cells in their requirement for Trx and in theresponse to CD40-stimulation. IL-2 and IL-15, in combination with Trx,induced proliferation of B-CLL cells from some patients with an advanceddisease in the absence of Ig-cross-linking by Staphylococcus aureus Cowanstrain 1 (SAC) particles. Further, the IL-2/IL-15+Trx or SAC+IL-2/IL-15+Trx-induced proliferation of B-CLL cells was inhibited by CD40-stimulation. Bythe sequential use of two protocols for induction of proliferation (i.e. SAC+IL-2+Trx and CD40-stimulation+IL-4+IL-10+Trx) B-CLL cells could be expandedand maintained in culture for more than one month in the absence of Epstein-Barr virus infection. Trx was found to inhibit apoptosis of in vitro cultured B-CLL cells, and the kinetics of survival correlated with an inhibition of Bcl-2down-regulation.