Resistance of T-cell acute lymphoblastic leukemia to tumor necrosis factor−related apoptosis-inducing ligand-mediated apoptosis

Akahane, Koshi; Inukai, Takeshi; Zhang, Xiaochun; Hirose, Kinuko; Kuroda, Itaru; Goi, Kumiko; Honna, Hiroko; Kagami, Keiko; Nakazawa, Shinpei; Endo, Kazushi; Kubota, Takeo; Yagita, Hideo; Koyama-Okazaki, Toshiko; Sugita, Kanji

doi:10.1016/j.exphem.2010.06.014

« Previous Next »Experimental Hematology
Volume 38, Issue 10 , Pages 885-895, October 2010

Resistance of T-cell acute lymphoblastic leukemia to tumor necrosis factor−related apoptosis-inducing ligand-mediated apoptosis

Koshi Akahane
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
Takeshi Inukai
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
- Offprint requests to: Takeshi Inukai, M.D., Department of Pediatrics, School of Medicine, University of Yamanashi, Tamaho, Nakakoma, Yamanashi 409-3898, Japan
Xiaochun Zhang
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
Kinuko Hirose
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
Itaru Kuroda
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
Kumiko Goi
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
Hiroko Honna
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
Keiko Kagami
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
Shinpei Nakazawa
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan
Kazushi Endo
- Department of Epigenetic Medicine, School of Medicine, University of Yamanashi, Yamanashi, Japan
Takeo Kubota
- Department of Epigenetic Medicine, School of Medicine, University of Yamanashi, Yamanashi, Japan
Hideo Yagita
- Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Toshiko Koyama-Okazaki
- Laboratory of Immunology, Saitama Shakaihoken Hospital, Saitama, Japan
Kanji Sugita
- Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan

Received 12 December 2009; received in revised form 24 June 2010; accepted 28 June 2010. published online 28 July 2010.

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.