LYMPHOTOXIN-ALPHA IS AN AUTOCRINE GROWTH-FACTOR FOR CHRONIC LYMPHOCYTIC-LEUKEMIA B-CELLS

Lymphotoxin-alpha (LT), also called TNF-beta, which belongs to the 'TN F family' was originally isolated from a lymphoblastoid cell line. LT enhances the proliferation of activated B cells and augments B cell pr oliferation induced by IL-2. It functions as an autocrine growth facto r for EBV-infected B cell lines and has been implicated in the pathoge nesis of B cell malignancies. We tested the expression of LT mRNA in B -CLL and found that LT was expressed in highly purified leukemic cells in 11 out of II patients examined. Regulation of expression of LT mRN A is aberrant in B-CLL cells, since LT mRNA expression was not detecte d in fresh peripheral blood mononuclear cells or B cells identified in seven out of seven normal individuals. In addition, LT mRNA expressio n was detected for up to 6 days in purified unstimulated in vitro cult ures of B-CLL cells. Glucocorticosteroids, that have been effectively used in the treatment of lymphoid malignancies, were added to the cult ures and abrogated the LT mRNA expression after an incubation time of 12 h. Addition of recombinant LT to cultures increased proliferation o f B-CLL cells while proliferation of these cells was inhibited by anti sense oligonucleotides against LT mRNA. B-CLL cells cultured with LT a ntisense oligonucleotides (asLT) as well as glucocorticoid-treated cel ls showed reduced viability and a DNA fragmentation ladder characteris tic of apoptosis suggesting a relationship between down-regulation of LT mRNA expression and the induction of apoptosis. These studies suppo rt the role of LT in the growth regulation and development of B-CLL ce lls.