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Differential Effects of a Stem Cell Factor-Immunoglobulin Fusion Protein on Malignant and Normal Hematopoietic Cells¹

Department of Hematology, Oncology and Transfusion Medicine, Universitaetsklinikum Benjamin Franklin, 12200 Berlin, Germany

We genetically connected the extracellular domain of human stem cell factor to the Fc-portion of human IgG1. The chimeric recombinant stem cell factor IgG1 fusion protein (rSCF-IgG1) had an apparent M_r 190,000 and consisted of three identical covalently linked subunits. It specifically bound to c-kit and the high affinity Fc receptor, respectively. Liquid phase rSCF-IgG1 was, on a molar basis, about eight times more potent than native human rSCF in stimulating the proliferation of c-kit-positive leukemic cell lines and of nonmalignant CD34-positive hematopoietic progenitor cells. Although the effective dose conferring half maximum of [methyl-³H]thymidine uptake by liquid phase and solid phase-bound rSCF-IgG1 were comparable, the plateau level of [methyl-³H]thymidine uptake by malignant cells was decreased by the latter, whereas proliferation of nonmalignant progenitor cells was supported. Liquid phase rSCF-IgG1 had a 2-fold increased potential to maintain primitive nonmalignant progenitor cells in stroma-free long-term culture compared with rSCF. Liquid phase rSCF-IgG1 caused enhanced and prolonged receptor phosphorylation and a more rapid down modulation of c-kit. Our data support the concept that solid phase-attachment of rSCF-IgG1 is sufficient for alteration of biological function and that rSCF-IgG1 partially blocks SCF-stimulated malignant cell growth while supporting normal progenitor cells.