Resistance of T-cell acute lymphoblastic leukemia to tumor necrosis factor−related apoptosis-inducing ligand-mediated apoptosis
Received 12 December 2009; received in revised form 24 June 2010; accepted 28 June 2010. published online 28 July 2010. Uncorrected Proof
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.
Conclusion
In contrast to higher sensitivity to FasL, T-ALL showed resistance to TRAIL, which might be responsible for resistance to TRAIL-mediated cellular immunity.
aDepartment of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
bDepartment of Epigenetic Medicine, School of Medicine, University of Yamanashi, Yamanashi, Japan
cDepartment of Immunology, Juntendo University School of Medicine, Tokyo, Japan
dLaboratory of Immunology, Saitama Shakaihoken Hospital, Saitama, Japan
Offprint requests to: Takeshi Inukai, M.D., Department of Pediatrics, School of Medicine, University of Yamanashi, Tamaho, Nakakoma, Yamanashi 409-3898, Japan
ABSTRACT