title: High TRAIL-R3 expression on leukemic blasts is associated with poor outcome and induces apoptosis-resistance which can be overcome by targeting TRAIL-R2.
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.
authors.affiliation: Department of Haematology, VU University Medical Centre, Amsterdam, The Netherlands. m.chamuleau@vumc.nl
authors.forename: M E D
authors.initials: ME
authors.lastname: Chamuleau
authors.forename: G J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: A
authors.initials: A
authors.lastname: van Rhenen
authors.forename: L
authors.initials: L
authors.lastname: van Dreunen
authors.forename: S M G
authors.initials: SM
authors.lastname: Jirka
authors.forename: A
authors.initials: A
authors.lastname: Zevenbergen
authors.forename: G J
authors.initials: GJ
authors.lastname: Schuurhuis
authors.forename: A A
authors.initials: AA
authors.lastname: van de Loosdrecht
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D018922:HL-60 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D016896:Treatment Outcome; D053319:Tumor Necrosis Factor Decoy Receptors / Q000096:biosynthesis*; D020298:U937 Cells; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058851:GPI-Linked Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; C510234:lexatumumab; C507357:mapatumumab