The Cytokine, Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF), Can Deliver Bcl-XL as an Extracellular Fusion Protein to Protect Cells from Apoptosis and Retain Differentiation Induction

Abstract

Bcl-XL, a member of the Bcl-2 protein family, is able to suppress cell death induced by diverse stimuli in many cell types, including hematopoietic cells. Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that promotes the proliferation and maturation of neutrophils, eosinophils, and macrophages from bone marrow progenitors. We fused GM-CSF to Bcl-XL and examined the capacity of this chimera to bind human cells through the GM-CSF receptor and prevent apoptosis. We found that the chimeric protein increased the proliferation of human monocytes in culture from 24 h until at least 72 h. In the presence of different apoptotic agents, GM-CSF-Bcl-XL protected cells from induced cell death and promoted proliferation, whereas GM-CSF alone was completely inhibited. In the presence of cytarabine, GM-CSF-Bcl-XL was able also to promote the differentiation of the CD34+ myeloid precursor whereas Lfn-Bcl-XL, lacking the GM-CSF domain-stimulated cell proliferation and not differentiation. We conclude that recombinant GM-CSF-Bcl-XL binds the GM-CSF receptor on human monocyte/macrophage cells and bone marrow progenitors inducing differentiation and allowing Bcl-XL entry into cells where it blocks cell death and allows amplified cell proliferation. This fully human fusion protein has potential to prevent monocytopenia and represents a new strategy for engineering anti-apoptotic therapeutics.