Differential effects of a stem cell factor-immunoglobulin fusion protein on malignant and normal hematopoietic cells

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 similar to M-r 190,000 and consisted of three identical covalently linked subunits, It specifically b ound to c-kit and the high affinity Fc gamma 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 leukem ic cell lines and of nonmalignant CD34-positive hematopoietic progenitor ce lls. Although the effective dose conferring half maximum of [methyl-H-3]thy midine uptake by liquid phase and solid phase-bound rSCF-IgG1 were comparab le, the plateau level of [methyl-H-3]thymidine uptake by malignant cells wa s decreased by the latter, whereas proliferation of nonmalignant progenitor cells was supported. Liquid phase rSCF-IgG1 had a 2-fold increased potenti al 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-k it, Our data support the concept that solid phase-attachment of rSCF-IgG1 i s sufficient for alteration of biological function and that rSCF-IgG1 parti ally blocks SCF-stimulated malignant cell growth while supporting normal pr ogenitor cells.