Tumor necrosis factor–related apoptosis-inducing ligand induces monocytic maturation of leukemic and normal myeloid precursors through a caspase-dependent pathway

• Published in: Blood Vol. 100; no. 7; pp. 2421 - 2429
• Main Authors: Secchiero, Paola, Gonelli, Arianna, Mirandola, Prisco, Melloni, Elisabetta, Zamai, Loris, Celeghini, Claudio, Milani, Daniela, Zauli, Giorgio
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-10-2002; The Americain Society of Hematology
• Subjects: Antigens, CD - analysis; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Regulatory Proteins; Base Sequence; Biological and medical sciences; Caspases - metabolism; CD11b Antigen - analysis; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell Survival; DNA Primers; Fundamental and applied biological sciences. Psychology; Hematologic and hematopoietic diseases; HL-60 Cells; Humans; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lipopolysaccharide Receptors - analysis; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Molecular and cellular biology; Monocytes - cytology; Polymerase Chain Reaction; Recombinant Proteins - metabolism; TNF-Related Apoptosis-Inducing Ligand; Transcription, Genetic; Transfection; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Enzyme; Cysteine endopeptidases; Leukemia; Caspase; Cytotoxicity; Malignant hemopathy; Myeloid cell; Biological activity; Ripening; Peptidases; Cell line; Hematopoiesis; Hydrolases; TNF related apoptosis inducing ligand; Myelopoiesis; Caspases
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-01-0047

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.