Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 2421-2429 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 100 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Oct 1 2002 |
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ASJC Scopus subject areas
- Hematology
Cite this
Tumor necrosis factor - Related apoptosis-inducing ligand induces monocytic maturation of leukemic and normal myeloid precursors through a caspase-dependent pathway. / Secchiero, Paola; Gonelli, Arianna; Mirandola, Prisco; Melloni, Elisabetta; Zamai, Loris; Celeghini, Claudio; Milani, Daniela; Zauli, Giorgio.
In: Blood, Vol. 100, No. 7, 01.10.2002, p. 2421-2429.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tumor necrosis factor - Related apoptosis-inducing ligand induces monocytic maturation of leukemic and normal myeloid precursors through a caspase-dependent pathway
AU - Secchiero, Paola
AU - Gonelli, Arianna
AU - Mirandola, Prisco
AU - Melloni, Elisabetta
AU - Zamai, Loris
AU - Celeghini, Claudio
AU - Milani, Daniela
AU - Zauli, Giorgio
PY - 2002/10/1
Y1 - 2002/10/1
N2 - 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.
AB - 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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U2 - 10.1182/blood-2002-01-0047
DO - 10.1182/blood-2002-01-0047
M3 - Article
VL - 100
SP - 2421
EP - 2429
JO - Blood
JF - Blood
SN - 0006-4971
IS - 7
ER -