TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) DOWN-REGULATES C-KIT PROTOONCOGENE PRODUCT EXPRESSION IN NORMAL AND ACUTE MYELOID-LEUKEMIA CD34(-ALPHA RECEPTORS() CELLS VIA P55 TNF)

Tumor necrosis factor alpha (TNF alpha), as a modulator of hematopoies is, interacts with many growth factor receptors, such as interleukin-3 , granulocyte-macrophage colony-stimulating factor (CSF), and granuloc yte-CSF receptors. Here, we studied the interactions between TNF alpha and the stem cell factor (SCF) receptor, c-kit, in normal CD34(+) hem atopoietic progenitors and their leukemic counterpart, ie, acute myelo id leukemic (AML) CD34(+) cells coexpressing c-kit antigen. The result s showed that (1) incubation of normal bone marrow mononuclear cells w ith 200 U/mL rhTNF alpha for 20 hours induced a diminution of 31.2% +/ - 5.2% of CD34(+) cells coexpressing c-kit; (2) the same decrease was observed using purified CD34(+) cells and, furthermore, their prolifer ative response to SCF was inhibited by 31.5% +/- 7.3% after exposure t o TNF alpha; (3) similar experiments performed on CD34(+) c-kit(+) AML cells from 11 patients gave comparable results. Further analysis at t he mRNA level indicated that TNF alpha decreased c-kit mRNA transcript s. Moreover, using monoclonal antibodies against the two types of TNF alpha receptors, p75 and p55, we showed that the downregulation of c-k it proto-oncogene product by TNF alpha, on normal and leukemic CD34(+) cells, was exclusively mediated by the TNF alpha p55 receptor. Theref ore, we conclude that TNF alpha acts as a downregulator of the SCF rec eptor expression. (C) 1994 by The American Society of Hematology.