Lymphotoxin-α is an autocrine growth factor for chronic lymphocytic leukemia B cells

Abstract

Lymphotoxin-alpha (LT), also called TNF-beta, which belongs to the ‘TNF family’ was originally isolated from a lymphoblastoid cell line. LT enhances the proliferation of activated B cells and augments B cell proliferation induced by IL-2. It functions as an autocrine growth factor for EBV-infected B cell lines and has been implicated in the pathogenesis 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 11 patients examined. Regulation of expression of LT mRNA is aberrant in B-CLL cells, since LT mRNA expression was not detected in fresh peripheral blood mononuclear cells or B cells identified in seven out of seven normal individuals. In addition, LT mRNA expression was detected for up to 6 days in purified unstimulated in vitro cultures of B-CLL cells. Glucocorticosteroids, that have been effectively used in the treatment of lymphoid malignancies, were added to the cultures and abrogated the LT mRNA expression after an incubation time of 12 h. Addition of recombinant LT to cultures increased proliferation of B-CLL cells while proliferation of these cells was inhibited by antisense oligonucleotides against LT mRNA. B-CLL cells cultured with LT antisense oligonucleotides (asLT) as well as glucocorticoid-treated cells showed reduced viability and a DNA fragmentation ladder characteristic of apoptosis suggesting a relationship between down-regulation of LT mRNA expression and the induction of apoptosis. These studies support the role of LT in the growth regulation and development of B-CLL cells.