1. Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors
- Author
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Keiko Kagami, Masao Kobayashi, Itaru Kuroda, Takeshi Inukai, Kinuko Hirose, Hidemitsu Kurosawa, Kozo Nakamura, Hiroaki Honda, Mikiya Endo, Kanji Sugita, Koshi Akahane, Toshiya Inaba, Hiroko Honna-Oshiro, Shinpei Nakazawa, A. Thomas Look, Hideo Yagita, Xiaochun Zhang, and Kumiko Goi
- Subjects
Transcriptional Activation ,Cancer Research ,Oncogene Proteins, Fusion ,Blotting, Western ,Apoptosis ,Electrophoretic Mobility Shift Assay ,Biology ,Real-Time Polymerase Chain Reaction ,Translocation, Genetic ,TNF-Related Apoptosis-Inducing Ligand ,Transactivation ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Humans ,Cytotoxic T cell ,RNA, Messenger ,Luciferases ,Promoter Regions, Genetic ,Receptor ,Cell Proliferation ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Up-Regulation ,DNA-Binding Proteins ,Transplantation ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,Oncology ,Cell culture ,Immunology ,Cancer research ,Stem cell ,Chromosomes, Human, Pair 19 ,Chromosomes, Human, Pair 17 ,Transcription Factors - Abstract
t(17;19)-acute lymphoblastic leukemia (ALL) shows extremely poor prognosis. E2A-HLF derived from t(17;19) blocks apoptosis induced by the intrinsic mitochondrial pathway and has a central role in leukemogenesis and chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed on cytotoxic T cells and natural killer cells and binds with death receptors (DR4/DR5), inducing apoptosis by dual activation of intrinsic and extrinsic pathways, and TRAIL mediates the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT). We found that cell lines and patients' samples of t(17;19)-ALL expressed death receptors for TRAIL, and recombinant soluble TRAIL immediately induced apoptosis into t(17;19)-ALL cell lines. E2A-HLF induced gene expression of DR4/DR5, which was dependent on the DNA-binding and transactivation activities of E2A-HLF through the 5' upstream region of the start site at least in the DR4 gene. Introduction of E2A-HLF into non-t(17;19)-ALL cell line upregulated DR4 and DR5 expression, and sensitized to proapoptotic activity of recombinant soluble TRAIL. Finally, a newly diagnosed t(17;19)-ALL patient underwent allo-SCT immediately after induction of first complete remission, and the patient has survived without relapse for over 3-1/2 years after allo-SCT. These findings suggest that E2A-HLF sensitizes t(17;19)-ALL to the GVL effect by upregulating death receptors for TRAIL.
- Published
- 2012
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