Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: a possible regulatory role of TNF in the progression of the disease

Abstract

Tumor necrosis factor-alpha (TNF) is a cytokine that displays a pleomorphic array of effects on different cell populations. Evidence is presented that TNF may be constitutively produced by B-cell chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) cells and that it may play a relevant role in these diseases. These conclusions are based on the presence of circulating levels of TNF in the serum of 20 of the 24 patients tested (83.3%), while undetectable values were found in normal sera. The suggestion that the increased serum levels were due to the leukemic cell population is strengthened by the evidence that purified B-CLL and HCL cells may constitutively release variable degrees of TNF. These levels markedly increase after incubation with interferon gamma or phytohemagglutinin (PHA) plus phorbol myristate acetate (PMA). The cellular release of TNF by primary B-CLL cells was significantly (P less than .001) higher in B-CLL stage O-I patients compared with stage II-III patients. The demonstration that, in B-cell chronic lymphoproliferative disorders, the pathologic cells may release TNF was further confirmed by the presence of the mRNA for this cytokine in primary and/or in pre-activated cells. Recombinant TNF was capable of inducing a proliferative signal only in a minority of cases (4/24); in most cases it was ineffective, and, in a few, it reduced the degree of proliferation. Furthermore, in costimulatory experiments with interleukin-2 and PHA plus PMA, TNF was ineffective. On the other hand, when primary B-CLL cells were incubated in the presence of an anti-TNF antibody, in 8 of 12 independent experiments a 2- to 15-fold increase in thymidine uptake was documented. Taken together, these results suggest that TNF may play a regulatory role in the progression of the neoplastic clone in B-cell chronic lymphoproliferative disorders and may be implicated in some of the side effects associated with these diseases.

ELEVATED CIRCULATING LEVELS OF TNFα AND ITS p55 SOLUBLE RECEPTOR ARE ASSOCIATED WITH AN ADVERSE PROGNOSIS IN LYMPHOMA PATIENTS

“…Moreover, recent data indicate that TNF constitutes an autocrine growth factor for normal B cells activated through their antigen receptor or the CD40 pathway (Boussiotis et al, 1994). Several reports indicate that malignant B cells in hairy cell leukaemia and chronic lymphocytic leukaemia are also able to produce TNF in an autocrine fashion (Cordingley et al, 1988;Digel et al, 1989;Foa et al, 1990). These studies demonstrated the cytokine production by these malignant cells isolated in vitro, and increased viability and thymidine incorporation of these cells upon TNF incubation.…”

Cells, cytokines, chemokines, and cancer stress: A biobehavioral study of patients with chronic lymphocytic leukemia

“…The association between stress and TNFa is particularly important in CLL, because malignant cells release TNFa spontaneously, 15 and TNFa increases their proliferation and viability. 52 The current TNFa finding adds to the biobehavioral cancer literature, because most studies have reported that depression, rather than stress, is related to higher levels of TNFa.…”

“…TNFa is increased in patients who have CLL compared with healthy individuals 15 and is correlated with higher white cell counts at diagnosis and shorter progression-free survival. 16,17 In vitro data reveal that CLL neoplastic lymphocytes release TNFa spontaneously 15 and that exposure to TNFa increases the proliferation and viability of leukemic lymphocytes. 18 A proliferation-inducing ligand (APRIL) and the Bcell-activating factor of the TNF family (BAFF) are cytokines that aid in the survival and proliferation of CLL cells.…”

Interferon‐alpha 2b (IFNα) for Early‐Phase Chronic Lymphocytic Leukaemia with High Risk for Disease Progression: Results of a Randomized Multicentre Study

“…tumour necrosis factor (TNF), IL-6, IL-1® and IL-1 has been demonstrated (Heslop et al, 1990). However, the role of TNF remains controversial as it may, itself, have antiproliferative effects (Foa et al, 1990). Furthermore, a deficiency of TNF production in CLL cells has been shown (Flieger et al, 1990;Dahlke et al, 1995).…”