GROWTH ARREST AND TERMINAL DIFFERENTIATION OF LEUKEMIC MYELOMONOCYTICCELLS INDUCED THROUGH LIGATION OF SURFACE CD23 ANTIGEN

Acute myelogenous leukemia (AML) cells express CD23 surface antigen af ter in vitro treatment with various cytokines, including interleukin-4 (IL-4) and interferon gamma. Subsequent ligation of CD23 by specific monoclonal antibody (MoAb) induces substantial morphologic and functio nal modifications in these cells. In the present study, we investigate d the role of CD23 in the proliferation and the maturation of leukemic cells from AML patients or the U937 cell line. CD23(+) cell treatment with CD23 MoAb inhibited the proliferation of leukemic cells. This co rrelated with their terminal differentiation after 7 to 9 days incubat ion because they (1) definitively lost their growth capacity; (2) adhe red to culture flasks and became monocyte/macrophage-like; and (3) exp ressed mature monocyte markers including nonspecific esterases. Intrac ellular mechanism of this antitumoral effect was then analyzed in U937 cells. Induction of high-density surface CD23 expression by IL-4 or g ranulocyte-macrophage colony-stimulating factor coincided with a trans ient decrease of U937 cell proliferation. CD23 ligation during this lo w-proliferative phase induced a rapid activation of L-arginine-depende nt pathway and the intracellular accumulation of cyclic guanosine mono phosphate and cyclic adenosine monophosphate (cAMP). Induction of thes e early messengers was followed by the activation of nuclear factor-kB transcription factor and the modulation of proto-oncogene expression by U937 cells. Whereas U937 cell treatment with IL-4 decreased c-fos/c -jun expression, CD23 MoAb reinduced c-fos/c-jun and promoted the expr ession of cell maturation-associated proto-oncogenes junB and c-fms, d uring the first 24 hours. Both IL-4 and CD23 MoAb downregulated the ex pression of c-myb. CD23 ligation also induced the production of TNF al pha by U937 cells. Inhibitors of cAMP and nitric oxide reversed CD23-m ediated modification in U937 cells. These data evidence the ability of CD23 surface antigen to mediate terminal differentiation of early leu kemic myelomonocytic cells. (C) 1994 by The American Society of Hemato logy.