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Differential Expression of Bcl-2 Homologs in Human CD34⁺ Hematopoietic Progenitor Cells Induced to Differentiate into Erythroid or Granulocytic Cells

^a Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway;
^b Institute of Medical Biochemistry, The University of Oslo, Oslo, Norway

Key Words. Hematopoiesis • Human • CD34⁺ cells • Erythropoiesis • Bcl-2 • Bcl-x_L • Apoptosis

Dag Josefsen, M.D., Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. Telephone: 47-22-93-45-69; Fax: 47-22-50-07-30; e-mail: dag.josefsen{at}labmed.uio.no

The Bcl-2 family of proteins has been shown to play a central role in the regulation of apoptosis. We have examined the expression of several Bcl-2 homologs upon stimulation of CD34⁺ human hematopoietic progenitor cells. CD34⁺ cells were induced to differentiate into predominantly erythroid cells in the presence of erythropoietin (Epo) and stem cell factor (SCF), while the addition of G-CSF and SCF led to differentiation predominantly into granulocytic cells, as demonstrated by immunophenotyping and morphological examination of cultured cells. In Epo- and SCF-stimulated cells, we found a marked increase in the level of Bcl-x_L protein expression and downregulation of Bax expression, apparent from day 4 and more pronounced on days 8 and 21. In contrast, Bcl-x_L protein expression was downregulated in G-CSF- and SCF-stimulated cells compared with cells cultured in medium alone, whereas there was no sign of change in the level of Bax. Mcl-1 expression showed a biphasic expression pattern in both early erythropoiesis and early granulopoiesis, but with an inverse regulation. Thus, Mcl-1 levels initially decreased in granulocytic progenitor cells and increased in erythroid progenitor cells. Finally, Bcl-2 expression was significantly downregulated in both Epo and SCF and G-CSF- and SCF-stimulated cells.

The role of the distinct upregulation of Bcl-x_L in early erythroid differentiation was further examined by use of specific ribozymes against Bcl-x_L. Addition of Bcl-x_L ribozymes promoted a clear increase in cell death of Epo- and SCF-stimulated cells, while erythroid differentiation was not affected. In conclusion, we found a distinct regulation of several Bcl-2 family members in CD34⁺ cells dependent on the cytokine stimulation given. The use of Bcl-x_L-specific ribozymes suggested that Bcl-x_L is important for survival but not for differentiation of erythroid progenitor cells.

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