Optimal proliferation of a hematopoietic progenitor cell line requires either costimulation with stem cell factor or increase of receptor expression that can be replaced by overexpression of Bcl-2

In vitro proliferation of hematopoietic stem cells requires costimulation b y multiple regulatory factors whereas expansion of lineage-committed progen itor cells generated by stem cells usually requires only a single factor. T he distinct requirement of factors for proliferation coincides with the dif ferential temporal expression of the subunits of cytokine receptors during early stem cell differentiation. In this study. we explored the underlying mechanism of the requirement of costimulation in a hematopoietic progenitor cell line TF-1. We found that granulocyte-macrophage colony-stimulating fa ctor (GM-CSF) optimally activated proliferation of TF-1 cells regardless of the presence or absence of stem cell factor (SCF). However, interleukin-5 (IL-5) alone sustained survival of TF-1 cells and required costimulation of SCF for optimal proliferation. The synergistic effect of SCF was partly du e to its anti-apoptosis activity. Overexpression of the IL-5 receptor or su bunit (IL5R alpha) in TF-1 cells by genetic selection or retroviral infecti on also resumed optimal proliferation due to correction of the defect in ap optosis suppression. Exogenous expression of an oncogenic anti-apoptosis pr otein, Bcl-2, conferred on TF-1 cells an Il-L-dependent phenotype, In summa ry, our data suggested SCF costimulation is only necessary when the express ion level of IL5R alpha is low and apoptosis suppression is defective in th e signal transduction of IL-5. Expression of Bcl-2 proteins released the gr owth restriction of the progenitor cells and may be implicated in leukemia formation. (C) 1999 by The American Society of Hematology.