title: Resistance of T-cell acute lymphoblastic leukemia to tumor necrosis factor--related apoptosis-inducing ligand-mediated apoptosis.
abstract: 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.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Akahane
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inukai
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Zhang
authors.forename: Kinuko
authors.initials: K
authors.lastname: Hirose
authors.forename: Itaru
authors.initials: I
authors.lastname: Kuroda
authors.forename: Kumiko
authors.initials: K
authors.lastname: Goi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Honna
authors.forename: Keiko
authors.initials: K
authors.lastname: Kagami
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakazawa
authors.forename: Kazushi
authors.initials: K
authors.lastname: Endo
authors.forename: Takeo
authors.initials: T
authors.lastname: Kubota
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Toshiko
authors.initials: T
authors.lastname: Koyama-Okazaki
authors.forename: Kanji
authors.initials: K
authors.lastname: Sugita
mesh_terms: 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
chemical_list: 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