High TRAIL-R3 expression on leukemic blasts is associated with poor outcome and induces apoptosis-resistance which can be overcome by targeting TRAIL-R2

• Published in: Leukemia research 2011-06, Vol.35 (6), p.741-749
• Main Authors: Chamuleau, M.E.D, Ossenkoppele, G.J, van Rhenen, A, van Dreunen, L, Jirka, S.M.G, Zevenbergen, A, Schuurhuis, G.J, van de Loosdrecht, A.A
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Adolescent; Adult; Aged; Antibodies, Monoclonal - pharmacology; Apoptosis; Apoptosis - drug effects; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Cell Line; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Female; GPI-Linked Proteins - biosynthesis; Hematology, Oncology and Palliative Medicine; HL-60 Cells; Human monoclonal antibodies; Humans; Immunotherapy; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Male; Middle Aged; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prognosis; Receptors, TNF-Related Apoptosis-Inducing Ligand - antagonists & inhibitors; Receptors, TNF-Related Apoptosis-Inducing Ligand - biosynthesis; Receptors, Tumor Necrosis Factor, Member 10c; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL; Treatment Outcome; Tumor Necrosis Factor Decoy Receptors - biosynthesis; U937 Cells; Young Adult
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2010.12.032

Abstract Activation of the TNF-related apoptosis-inducing ligand (TRAIL) pathway can induce apoptosis in a broad range of human cancer cells. Four membrane-bound receptors have been identified. TRAIL-R1 and TRAIL-R2 contain a functional death domain; TRAIL-R3 and TRAIL-R4 lack a functional death domain and function as decoy receptors. Flow-cytometric analysis revealed that acute myeloid leukemic (AML) blasts expressed significantly more pro-apoptotic receptors compared to normal blasts. However, about 20% of AML patients highly expressed decoy receptor TRAIL-R3, which was strongly correlated to a shortened overall survival. TRAIL-R3 expression was also high on CD34+/CD38− cells, the compartment that harbors the leukemia initiating stem cell. Expression levels of pro-apoptotic TRAIL receptors were not correlated to the susceptibility for soluble TRAIL, which was generally low (mean level of cell death induction 14%). Cell death could be enhanced by down-modulation of TRAIL-R3, confirming its decoy function on AML blasts. Bypassing of TRAIL-R3 by treatment with antibodies directly targeting TRAIL-R2 resulted in higher rates of induced cell death (max. 80%). In conclusion, AML blasts do express pro-apoptotic TRAIL receptors. However, co-expression of decoy receptor TRAIL-R3 results in significant shortened overall survival. AML blasts could be targeted by anti-TRAIL-R2 antibodies, yielding a new therapeutic option for AML patients.