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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3716-3724
TNF-related apoptosis-inducing ligand (TRAIL) as a
negative regulator of normal human erythropoiesis
Loris Zamai,
Paola Secchiero,
Sabina Pierpaoli,
Alessandra Bassini,
Stefano Papa,
Emad S. Alnemri,
Lia Guidotti,
Marco Vitale, and
Giorgio Zauli
From the Institute of Morphological Sciences, University of Urbino,
Urbino, Italy; Department of Morphology and Embryology, Human Anatomy
Section, University of Ferrara, Ferrara, Italy; Institute of Histology
and General Embryology, University of Bologna, Bologna, Italy; Kimmel
Cancer Institute, Jefferson Medical College, Philadelphia,
Pennsylvania; Department of Biomedical Sciences and Biotechnologies,
Human Anatomy Section, University of Brescia, Brescia, Italy; Institute
of Cytomorphology NP CNR, c/o "Codivilla-Putti" Research
Institute, Bologna, Italy; and the Institute of Human Morphology,
"G. D'Annunzio," University of Chieti, Chieti, Italy.
The impact of tumor necrosis factor (TNF)-related apoptosis-inducing
ligand (TRAIL) on normal hematopoietic development was investigated
using adult peripheral blood CD34+ hematopoietic
progenitor cells, induced to differentiate along the erythroid,
megakaryocytic, granulocytic, and monocytic lineages by the addition of
specific cytokine cocktails. TRAIL selectively reduced the number of
erythroblasts, showing intermediate levels of glycophorin A
(glycophorin Ainterm) surface expression, which appeared in
liquid cultures supplemented with stem cell factor + interleukin
3 + erythropoietin at days 7-10. However, neither immature (day 4)
glycophorin Adim erythroid cells nor mature (day 14)
glycophorin Abright erythroblasts were sensitive to
TRAIL-mediated apoptosis. Moreover, pre-exposure to TRAIL significantly
decreased the number and size of erythroid colonies in semisolid
assays. These adverse effects of TRAIL were selective for
erythropoiesis, as TRAIL did not significantly influence the survival
of cells differentiating along the megakaryocytic, granulocytic, or
monocytic lineages. Furthermore, TRAIL was detected by Western blot
analysis in lysates obtained from normal bone marrow mononuclear cells.
These findings indicate that TRAIL acts in a lineage- and stage of
differentiation-specific manner, as a negative regulator of normal erythropoiesis.
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