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Product of the Steel Locus Can Replace Leukemic Cell Interaction¹

Laboratory of Hemopoiesis and Leukemia, Clinical Research Institute of Montreal, and Department of Medicine, University of Montreal, Montreal, Québec, Canada

Mutations in the Steel locus, encoding a growth factor (Steel factor or SF) or c-kit, the gene encoding its receptor, result in severe anemia in the mouse. In the present study, we have addressed the mechanism of synergistic growth activation, at the cellular level, by SF and GM-CSF using the blast cells of acute myeloblastic leukemia (AML blasts). Our data indicate that SF drastically alleviates the requirement in cell interaction for blast colony formation in most of the samples tested. Analysis of cultures performed in the presence of SF and GM-CSF at different cell concentrations, ranging from 1,000 to 20,000 cells, suggested a single limiting element, i.e., the blast clonogenic cell, while 2 or more limiting elements were found in cultures stimulated with GM-CSF alone, suggesting interacting cell populations. The presence of membrane-bound SF was detected by immunofluorescence, suggesting the possibility that secreted or membrane-bound SF may, at least in part, contribute to the density-dependent growth of AML blasts.

In all samples tested, SF appears to increase the responsiveness of AML blasts to GM-CSF, as demonstrated by a 3-fold decrease of GM-CSF half efficient concentration on addition of SF to the cultures. Exposure of AML blasts to SF did not affect GM-CSF receptor expression, suggesting that this increase in GM-CSF responsiveness is likely to occur at the postreceptor level. Interestingly, 2 of 15 AML samples surveyed did not respond to SF, and were both of the myelomonocytic or monocytic subtype, classified as M4 and M5, respectively.

¹ This work was supported by a grant from the National Cancer Institute of Canada (T. H.) and a studentship award of the National Autonomous University of Mexico and of the University of Montreal (J. R. C-C.). T. H. is a scholar of the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed, at Laboratory of Hemopoiesis and Leukemia, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Québec, Canada H2W 1R7.

Received 2/ 6/92. Accepted 7/22/92.

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