TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL.
OBJECTIVE
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, many cancer cells are resistant to apoptosis induction by TRAIL. The present study was designed to evaluate the sensitivity to TRAIL-induced apoptosis in acute myeloblastic leukemias (AML).


METHODS
TRAIL/TRAIL receptor (TRAIL-R) expression and sensitivity to TRAIL-mediated apoptosis were explored in 79 AML patients, including 17 patients with acute promyelocytic leukemia (APL).


RESULTS
In non-APL AML we observed frequent expression of TRAIL decoy receptors (TRAIL-R3 and TRAIL-R4), while TRAIL-R1 and TRAIL-R2 expression was restricted to AML exhibiting monocytic features. Total leukemic blasts, as well as AML colony-forming units (AML-CFU), were invariably resistant to TRAIL-mediated apoptosis. APL express membrane-bound TRAIL on their surface and exhibit a pattern of TRAIL-R expression similar to that observed in the other types of AML. Before, during and after retinoic acid treatment APL cells are TRAIL-resistant. The induction of granulocytic maturation of APL cells by retinoic acid was associated with a marked decline of TRAIL expression.


CONCLUSIONS
The analysis of experimental APL models (i.e., U937 cells engineered to express PML/RAR-Eo and NB4 cells) provided evidence that PML/RAR-Eo expression was associated with downmodulation of TRAIL-R1 and with resistance to TRAIL-mediated apoptosis. We suggest that AML blasts, including APL blasts, are resistant to TRAIL-mediated apoptosis, a phenomenon seemingly related to the expression of TRAIL decoy receptors on these cells. Finally, APL blasts express membrane-bound TRAIL that could confer an immunologic privilege to these cells.
Riccioni
Roberta
R
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Pasquini
Luca
L
Mariani
Gualtiero
G
Saulle
Ernestina
E
Rossini
Annalisa
A
Diverio
Daniela
D
Pelosi
Elvira
E
Vitale
Antonella
A
Chierichini
Anna
A
Cedrone
Michele
M
Foà
Robin
R
Lo Coco
Francesco
F
Peschle
Cesare
C
Testa
Ugo
U
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000032:analysis; D053181:Caspase 8 / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins; D006098:Granulocytes / Q000187:drug effects; D018922:HL-60 Cells / Q000473:pathology; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D053319:Tumor Necrosis Factor Decoy Receptors / Q000502:physiology*; D014410:Tumor Stem Cell Assay; D020298:U937 Cells / Q000187:drug effects
D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D015514:Oncogene Proteins, Fusion; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D011993:Recombinant Fusion Proteins; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D003561:Cytarabine; D014212:Tretinoin; D005047:Etoposide; D053148:Caspase 3; D053181:Caspase 8; D006918:Hydroxyurea