Expression and regulation of c-kit receptor and proliferative response to stem cell factor in childhood lymphoma and leukemia cells

The product of the protooncogene c-kit is a receptor tyrosine kinase for the hematopoietic cytokine stem cell factor (SCF). This cytokine is involved in the regulation of normal and neoplastic hematopoiesis, and synergizes with IL-7 to enhance the proliferation of preB-cells and thymocytes. To examine whether c-kif is involved in the pathogenesis of human leukemic cells, we investigated the expression and regulation of c-kit in childhood Burkitt's lymphoma (BL) and in T-lymphoblastic cells, as well as the mitogenic activity of recombinant human (rh) SCF on these cells. A panel of Epstein-Barr Virus (EBV) positive and negative BL cell lines, biopsy tumor cells from patients with Burkitt's lymphoma, T acute lymphoblastic leukemia (ALL) and T lymphoblastic non Hodgkin's lymphoma (LB-T NHL) were investigated. To study inducibility of c-kit receptor, the cells were cultured and stimulated by IL-7, PMA, and calcium ionophore A23187. c-kit expression was studied by RT-PCR followed by Southern blot analysis, fluorescence activated cell sorting (FACS) and by crosslinking of digoxigenin-labeled rhSCF to the cell surface. Proliferation of BL cell lines and T-lymphoblastic cells was measured under serum-free conditions in the presence and absence of rhSCF. c-kit receptors were detected by FACS analysis in 3 out of 13 investigated LB-T-NHL, in 2 T-ALL biopsy tumor cells and in none out of the 7 biopsy BL cells investigated. Low level expression of c-kit mRNA was only detecable by RT-PCR followed by Southern blot analysis in 2 of 13 cultured BL cell lines. c-kit mRNA or receptor upregulation could be demonstrated with IL-7 or A23187 and downregulation with PMA in BL and T-ALL cells. No stimulation or inhibition by rhSCF was observed in BL and LB-T NHL cells. Two of the c-kit positive T-ALL cells responded to rhSCF in a dose dependent manner. Normal peripheral B and T cells showed no c-kit transcripts detectable by RT-PCR followed by Southern blot analysis. These results suggest that c-kit receptors can be expressed at different levels in childhood B and T malignant cells and that the induction of c-kit by different reagents leads to a functional protein in childhood T-lymphoblastic cells but not in BL cells. We conclude that SCF can be a growth factor for T-lymphoblastic malignant cells but not BL cells.