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.

MATERIALS AND 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: Koshi Akahane, Takeshi Inukai, Xiaochun Zhang, Kinuko Hirose, Itaru Kuroda, Kumiko Goi, Hiroko Honna, Keiko Kagami, Shinpei Nakazawa, Kazushi Endo, Takeo Kubota, Hideo Yagita, Toshiko Koyama-Okazaki, Kanji Sugita
• Journal: Experimental hematology (Exp Hematol) Vol. 38 Issue 10 Pg. 885-95 (Oct 2010) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 20670671 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• FAS protein, human
• Fas Ligand Protein
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• fas Receptor
• Luciferases

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cells, Cultured
• DNA Methylation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance
• Fas Ligand Protein (pharmacology)
• Flow Cytometry
• Gene Expression (drug effects)
• Humans
• Immunoblotting
• Jurkat Cells
• Luciferases (genetics, metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism, pathology)
• Promoter Regions, Genetic (genetics)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• fas Receptor (metabolism)