Resistance of T-cell acute lymphoblastic leukemia to tumor necrosis factor--related apoptosis-inducing ligand-mediated apoptosis.
OBJECTIVE
Cytotoxic ligands are involved in tumor immunity and graft-vs.-leukemia effect after allogeneic stem cell transplantation for leukemia. To clarify the susceptibility of T-cell acute lymphoblastic leukemia (T-ALL) to tumor immunity, sensitivity to recombinant human soluble Fas ligand (rhsFasL) and tumor necrosis factor-related apoptosis-inducing ligand (rhsTRAIL) was determined.


METHODS
Sensitivity to rhsFasL and rhsTRAIL and cell surface expression of their receptors were tested in T-ALL cell lines (n = 7) and patients' samples (n = 17) and compared with those in B-precursor ALL cell lines (n = 30). Expression of components of the death-inducing signaling complex and the TRAIL receptor genes (DR4/DR5), and the methylation status and promoter activity of the DR4/DR5 gene were tested in T-ALL cell lines.


RESULTS
T-ALL cell lines showed higher level of Fas expression and higher sensitivity to rhsFasL than did B-precursor ALL cell lines. Despite comparable expression of components of death-inducing signaling complex, cell lines and patients' samples of T-ALL showed TRAIL-resistance associated with low cell surface expression of DR4/DR5. Gene expression of DR4/DR5 in T-ALL cell lines was significantly lower than that in B-precursor ALL cell lines, and the methylation status of the gene promoter in T-ALL cell lines was associated with the gene expression level at least for DR4. The demethylating agent, 5-aza 2'deoxycytidine, upregulated the gene expression of DR4/DR5, but was insufficient for their surface expression due to low basal promoter activity.


CONCLUSIONS
In contrast to higher sensitivity to FasL, T-ALL showed resistance to TRAIL, which might be responsible for resistance to TRAIL-mediated cellular immunity.
Akahane
Koshi
K
Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
Inukai
Takeshi
T
Zhang
Xiaochun
X
Hirose
Kinuko
K
Kuroda
Itaru
I
Goi
Kumiko
K
Honna
Hiroko
H
Kagami
Keiko
K
Nakazawa
Shinpei
S
Endo
Kazushi
K
Kubota
Takeo
T
Yagita
Hideo
H
Koyama-Okazaki
Toshiko
T
Sugita
Kanji
K
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D053222:Fas Ligand Protein / Q000494:pharmacology*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
C491901:FAS protein, human; D053222:Fas Ligand Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D019014:fas Receptor; D008156:Luciferases