BCR-ABL regulates death receptor expression for TNF-related apoptosis-inducing ligand (TRAIL) in Philadelphia chromosome-positive leukemia.
Allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for chronic myeloid leukemia and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia, and the graft-vs-leukemia (GVL) effect can eradicate residual leukemia after allo-SCT. Ph(+) leukemia cells frequently express death-inducing receptors (DR4 and DR5) for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the cytotoxic ligands expressed on cytotoxic T cells and natural killer cells mediating the GVL effect. Here we demonstrate that imatinib specifically downregulated DR4 and DR5 expression in cell lines and clinical samples of Ph(+) leukemia. Second-generation tyrosine kinase inhibitors (dasatinib and nilotinib) and short hairpin RNA against bcr-abl also downregulated DR4 and DR5 expression in Ph(+) leukemia cells, and transfection of bcr-abl into a Ph(-) leukemia cell line induced DR4 and DR5 expression, which was abrogated by imatinib treatment. Accordingly, Ph(+) leukemia cells that had been pretreated with imatinib showed resistance to the pro-apoptotic activity of recombinant human soluble TRAIL. These observations demonstrate that BCR-ABL is critically involved in the leukemia-specific expression of DR4 and DR5 and in the susceptibility of Ph(+) leukemia to TRAIL-mediated anti-leukemic activity, providing new insight into the mechanisms of the tumor-specific cytotoxic activities of TRAIL.
Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
I
I
Kuroda
T
T
Inukai
X
X
Zhang
J
J
Kikuchi
Y
Y
Furukawa
A
A
Nemoto
K
K
Akahane
K
K
Hirose
H
H
Honna-Oshiro
K
K
Goi
K
K
Kagami
H
H
Yagita
T
T
Tauchi
Y
Y
Maeda
K
K
Sugita
D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D053218:Receptors, Death Domain / Q000235:genetics* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D016044:Fusion Proteins, bcr-abl; D048052:Mitogen-Activated Protein Kinase 3