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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2002-01-0047.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2421-2429
HEMATOPOIESIS
Tumor necrosis factor-related apoptosis-inducing ligand induces
monocytic maturation of leukemic and normal myeloid precursors through
a caspase-dependent pathway
Paola Secchiero,
Arianna Gonelli,
Prisco Mirandola,
Elisabetta Melloni,
Loris Zamai,
Claudio Celeghini,
Daniela Milani, and
Giorgio Zauli
From the Department of Morphology and Embryology, Human
Anatomy Section, University of Ferrara; Institute of Morphological
Sciences, University of Urbino; and the Department of Human Normal
Morphology, University of Trieste, Italy.
Treatment of the human HL-60 cell line with tumor necrosis factor
(TNF)-related apoptosis-inducing ligand (TRAIL) resulted in rapid
(6-24 hours) cytotoxicity associated with progressive maturation of the
surviving cells along the monocytic lineage. The occurrence of
monocytic maturation was demonstrated by a significant increase of both
CD14 and CD11b surface expression, the acquisition of morphologic
features typical of mature monocytes, and phagocytic capacity in
TRAIL-treated cultures. By using selective pharmacologic inhibitors, it
was possible to demonstrate that activation of the caspase cascade
played a crucial role in mediating TRAIL cytotoxicity and monocytic
maturation of HL-60 cells. Moreover, experiments performed using
agonistic polyclonal antibodies, which mimic the interactions between
TRAIL and each TRAIL receptor, indicated that TRAIL-R1 was responsible
for mediating the TRAIL-induced maturation. Importantly, the
maturational effects of TRAIL were observed also in primary normal
CD34+ cells, seeded in serum-free liquid cultures for 4 to
8 days in the presence of SCF + GM CSF. After treatment with
TRAIL for 3 additional days, a significant increase in CD14 and CD11b
expression, coupled with an increased number of mature monocytes and
macrophages, was noticed in the absence of cytotoxicity. These data
disclose a novel role for TRAIL as a positive regulator of myeloid
differentiation. Moreover, the dichotomous effect of TRAIL on malignant
cells (early induction of apoptosis and monocytic maturation of the
surviving cells) might have important therapeutic implications for the
treatment of acute myeloid leukemia.

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