Tumor-necrosis-factor-related apoptosis-inducing ligand and the regulation of hematopoiesis.
OBJECTIVE
This review will focus on the emerging role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL-receptors in the pathophysiology of hematopoiesis and on the potential therapeutic applications of either recombinant TRAIL or anti-TRAIL-R1/-R2 agonistic antibodies for the treatment of hematological malignancies.


RESULTS
While CD34 stem/progenitor cells do not express TRAIL-receptors and are protected from TRAIL-induced apoptosis, accumulating evidence points to a role for elevated expression/release of TRAIL at the bone marrow level in the pathophysiology of aplastic anemia, Fanconi anemia, and myelodysplastic syndromes. In-vitro data show promising synergistic effects of recombinant TRAIL in association with proteasome or histone deacetylase inhibitors, natural compounds or small molecules in the therapy of myeloid and lymphoid malignancies. Moreover, although both recombinant TRAIL and anti-TRAIL-R1/-R2 antibodies are well tolerated in vivo, anti-TRAIL-R1/-R2 agonistic antibodies show the potential advantage of avoiding the neutralizing activity of the soluble receptor osteoprotegerin.


CONCLUSIONS
While a chronic pathological elevation of TRAIL at the bone marrow level might contribute to the impairment of normal hematopoiesis, the use of recombinant TRAIL and anti-TRAIL-R1/-R2 agonistic antibodies appears particularly promising for the treatment of hematological malignancies in particular, of multiple myeloma, especially if used in association with innovative therapeutic compounds.
Secchiero
Paola
P
Department of Morphology and Embryology, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy. secchier@mail.umbi.umd.edu
Zauli
Giorgio
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001853:Bone Marrow / Q000502:physiology; D003131:Combined Modality Therapy; D006402:Hematologic Diseases / Q000503:physiopathology; D019337:Hematologic Neoplasms / Q000628:therapy; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D053244:Osteoprotegerin / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000276:immunology / Q000502:physiology; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use
D053244:Osteoprotegerin; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse