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Tumor necrosis factor alpha (TNF alpha) downregulates c-kit proto- oncogene
product expression in normal and acute myeloid leukemia CD34+ cells via p55
TNF alpha receptors
E Khoury, C Andre, S Pontvert-Delucq, B Drenou, C Baillou, M Guigon, A Najman and FM Lemoine
Department of Hematology, Faculte de Medecine Saint Antoine, Paris, France.
Tumor necrosis factor alpha (TNF alpha), as a modulator of hematopoiesis,
interacts with many growth factor receptors, such as interleukin-3,
granulocyte-macrophage colony-stimulating factor (CSF), and granulocyte-CSF
receptors. Here, we studied the interactions between TNF alpha and the stem
cell factor (SCF) receptor, c-kit, in normal CD34+ hematopoietic
progenitors and their leukemic counterpart, ie, acute myeloid leukemic
(AML) CD34+ cells coexpressing c-kit antigen. The results showed that (1)
incubation of normal bone marrow mononuclear cells with 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 proliferative response to SCF was inhibited
by 31.5% +/- 7.3% after exposure to TNF alpha; (3) similar experiments
performed on CD34+ c-kit+ AML cells from 11 patients gave comparable
results. Further analysis at the mRNA level indicated that TNF alpha
decreased c-kit mRNA transcripts. Moreover, using monoclonal antibodies
against the two types of TNF alpha receptors, p75 and p55, we showed that
the downregulation of c-kit proto-oncogene product by TNF alpha, on normal
and leukemic CD34+ cells, was exclusively mediated by the TNF alpha p55
receptor. Therefore, we conclude that TNF alpha acts as a downregulator of
the SCF receptor expression.
Volume 84,
Issue 8,
pp. 2506-2514,
10/15/1994
Copyright © 1994 by The American Society of Hematology
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