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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2002-01-0047.
Submitted January 15, 2002
Accepted May 14, 2002
TNF-related apoptosis-inducing ligand (TRAIL) induces monocytic maturation of both leukemic and normal myeloid precursors via a caspase-dependent pathway
Paola Secchiero*, Arianna Gonelli, Prisco Mirandola, Elisabetta Melloni, Loris Zamai, Claudio Celeghini, Daniela Milani, and Giorgio Zauli
Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Ferrara, Italy
Institute of Morphological Sciences, University of Urbino, Urbino, Italy
Department of Human Normal Morphology, University of Trieste, Trieste, Italy
* Corresponding author; email: secchier{at}mail.umbi.umd.edu.
Treatment of the human HL-60 cell line with TNF-related apoptosis-inducing ligand (TRAIL) resulted in rapid (6-24 hours) cytotoxicity associated to progressive maturation of the surviving cells along the monocytic lineage. The occurrence of monocytic maturation was demonstrated by: i) a significant increase of both CD14 and CD11b surface expression, ii) the acquisition of morphological features typical of mature monocytes, and iii) of phagocytic capacity in TRAIL-treated cultures. By using selective pharmacological inhibitors, it was possible to demonstrate that activation of the caspase cascade played a crucial role in mediating both 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 4-8 days in the presence of SCF + GM-CSF. After treatment with TRAIL for additional 3 days, a significant increase of CD14 and CD11b expression coupled to 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 leukemias.
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