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Effects of Recombinant Human Tumor Necrosis Factor on Highly Enriched Hematopoietic Progenitor Cell Populations from Normal Human Bone Marrow and Peripheral Blood and Bone Marrow from Patients with Chronic Myeloid Leukemia¹

Laboratory of Hematopoietic Cell Kinetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Previous studies using unseparated normal human bone marrow cells have indicated that recombinant tumor necrosis factor (rTNF-) can inhibit the in vitro colony growth by normal granulocyte/macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells in a dose-dependent manner. In the present studies, by using very low numbers of highly enriched normal bone marrow progenitor cell populations as target cells, we have extended these previous findings to provide convincing evidence that erythroid and myeloid colony growth suppression by rTNF- is manifested by a direct interaction between rTNF- and CFU-GM and BFU-E progenitor cells.

In addition, the sensitivity of normal peripheral blood and chronic myeloid leukemia bone marrow CFU-GM and BFU-E colony growth to inhibition by rTNF- was examined and found to be comparable with that of normal bone marrow CFU-GM and BFU-E.

Although the continuous presence of high doses of rTNF- (5000 units/ml) was required in methylcellulose cultures for maximal CFU-GM (90%) and BFU-E (70%) colony suppression, short-term exposure (24 to 72 hr) of normal bone marrow-enriched progenitor cells to rTNF-, in the absence of hematopoietic growth factors, was sufficient to irreversibly suppress up to 50 to 65% of CFU-GM colony growth. In contrast, the number of BFU-E colonies was increased under these conditions. If, however, hematopoietic growth factors (Mo-T-cell-conditioned medium and erythropoietin) were present during preincubation of the cells with rTNF-, BFU-E were then slightly suppressed while the extent of CFU-GM inhibition remained essentially the same.

The suppressive effect of rTNF- on erythroid and myeloid progenitor cell growth appears to be most pronounced on the more primative stages of committed progenitor cell development, since inhibition of CFU-GM- and BFU-E-derived colony growth progressively decreased with the delayed addition of rTNF- to methylcellulose cultures.

[³H]Thymidine incorporation was also inhibited by rTNF- in normal bone marrow-enriched progenitor cell populations stimulated to proliferate in liquid culture by colony-stimulating factors. This effect was transient, however, since the activity of rTNF- declined after the first 24 h of culture at 37°C, particularly at low doses of rTNF- where the activity was completely lost after 48 h of culture. This loss of activity appeared to be due to a decreased sensitivity of progenitor cells to the antiproliferative effects of tumor necrosis factor (TNF) after an initial exposure rather than a lack of available TNF.

The use of purified hematopoietic progenitor cells should facilitate further studies in elucidating the interactions occurring between TNF and these cells at the cellular level as well as molecular level.

¹ Supported in part by National Cancer Institute Grants CA-19117, CA-08748, and CA-20194 and by the United Leukemia Fund.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

Received 2/27/87. Revised 5/28/87. Accepted 6/17/87.

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