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

Abstract

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.

Growth factor receptor profile of CD34+ cells in normal bone marrow, cord blood and mobilized peripheral blood

“…The low SCFR levels on the CD34 + cells in mobilized peripheral blood may also be partially due to the action of tumour necrosis factor (TNF)‐ α . The serum levels of this cytokine rise after administration of G‐CSF (30, 31) and TNF‐ α is able to down‐regulate m‐RNA and membrane protein levels of SCFR in CD34 + bone marrow cells (10).…”

“…We also investigated whether differences between the growth factor receptor profile of CD34 + cells from bone marrow and mobilized peripheral blood were due to the preferential mobilization of a particular CD34 + subset or to changes of the receptor expression induced by the mobilization procedure. Transcriptional regulation (10), shedding (11), ligand‐induced internalization (12) and proteolytic cleavage of receptors by neutrophil proteases (13) are some of the mechanisms which may be involved here. First, we determined the growth factor receptor expression of B‐lymphoid and early and late myeloid CD34 + precursors in bone marrow and compared these phenotypes with that found on CD34 + cells from mobilized peripheral blood.…”

Expression and modulation of cellular receptors for interferon‐γ, tumour necrosis factor, and Fas on human bone marrow CD34+ cells

“…These results suggest that both types of TNF-Rs may be differentially regulated and mediate distinct biological effects. For example, triggering of TNFR1 mediates a decrease in c-kit expression as well as enhancement of Fas-R expression on CD34 þ cells by TNF-a (Rusten et al, 1994b;Khoury et al, 1994;Nagafuji et al, 1995), and TNFR2 seems not to be involved in these functions.…”

“…Two types of TNF receptors have been found: TNFR1, the p55 chain, and TNFR2, the p75 chain. Whereas TNFR1 mediates the inhibitory effects of TNF-a on CD34 þ cells, TNFR2 can, under specific conditions, transduce stimulatory signals (Rusten et al, 1994b;Khoury et al, 1994). TNFR1 and Fas-R share a common 'death domain' (Nagata & Golstein, 1995).…”

Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition

“…1C) and was consistently found to be increased in hTERT-MUTZ3/10BTZ as compared to unexposed progenitor cells, indicative of enhanced early differentiation events. Next, we also determined the expression of cytokine receptors involved in DC differentiation (TNF-RI and -RII) and DC precursor proliferation (cKIT/CD117 and IL-3R/CD123) [26,27], under normal conditions or BTZ exposure at 10 nM, between passages 58 and 95. As shown in Fig.…”