GROWTH POTENTIATING ACTIVITY OF ENDOGENOUS PRODUCTION OF INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR-ALPHA IN BLAST CELLS OF ACUTE MYELOBLASTIC-LEUKEMIA

For the optimal growth of clonogenic cells in acute myeloblastic leuke mia (AML), several cytokines such as tumor necrosis factor alpha (TNF- alpha), interleukin-1 (IL-1) and IL-6 are required in addition to colo ny-stimulating factor (CSF), which may be produced by blast cells them selves. In the present study, we addressed the potential role of endog enous production of TNF-alpha and/or IL-1 in the in vitro growth of AM L clonogenic cells supported by IL-3. Addition of a specific neutraliz ing antibody against TNF-alpha (anti-TNF-alpha) to the culture signifi cantly reduced the growth-stimulating effect of IL-3 on the cells in 1 1 of 14 patients. Simultaneous addition of anti-IL-1 alpha and anti-IL -1 alpha also partly affected the growth, although to a much lesser ex tent when Compared to the effect observed with anti-TNF-alpha. In 3 pa tients, the growth-stimulating effect of IL-3 was completely abrogated by anti-TNF-alpha or a combination of all three antibodies. Constitut ive TNF-alpha transcript was observed in 5 patients and TNF-alpha prot ein was present in culture supernatant. Following in vitro culture, a transient but profound increase in c-fos, c-jun, TNF-alpha and IL-1 be ta mRNA levels was observed. Anti-TNF-alpha inhibited the accumulation of TNF-alpha transcript, suggesting that membrane-integrated TNF-alph a may be partly responsible for the induction of TNF-alpha mRNA. It se ems likely that the accumulation of these genes occurs through a prote in kinase C-independent signaling pathway.