Molecular Biology Of Mast Cell Growth &Differentiation

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Abstract

We have reported that human mast cells derive from a CD34+, Kit+, CD13+ pluripotent cell population. To further characterize the development of mast cell from these cells we have investigated the expression of telomerase activity in cultured human peripheral blood CD34+/CD117+/CD13+ progenitor cells for induction of telomerase associated with clonal expansion. A rapid increase in telomerase activity did preceed proliferation. The induction was transient, and telomerase activity declined to basal levels well before the appearance of mature mast cells. Tumor mast cell lines, in contrast, expressed persistently high telomerase activity throughout the cell cycle (collaboration with Dr. Beaven) In follow-up to our interest in stem cell factor (SCF), we addressed the role of the Src family member Lyn in SCF-mediated responses. A dominant inhibitory Lyn mutant and Lyn-deficient mice were employed. SCF-induced proliferation was found to be reduced in Lyn-deficient mast cells and SCF-responsive progenitor cells; demonstrating that Lyn is required for normal SCF-induced growth (collaboration with Dr. Linnekin). We also examined whether SCF acts as a survival factor through the regulation of the Bcl-2 family of apoptosis-regulatory genes. Elimination of SCF from human mast cell cultures resulted in a significant apoptotic process, with down-regulation of the two apoptosis-regulatory proteins Bcl-2 and Bcl-XL. Deregulated expression of these two proteins was found in human mast cells lines which are SCF-independent. Thus, SCF functions as a survival factor by repressing apoptosis of human mast cells through Bcl-2 and Bcl-XL (collaboration with Dr. Mekori).