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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Zhang X, Inukai T, Hirose K, Akahane K, Kuroda I, Honna-Oshiro H, Kagami K, Goi K, Nakamura K, Kobayashi M, Endo M, Yagita H, Kurosawa H, Thomas Look A, Honda H, Inaba T, Nakazawa S, and Sugita K
- Subjects
- Blotting, Western, Cell Proliferation, DNA-Binding Proteins metabolism, Electrophoretic Mobility Shift Assay, Humans, Luciferases metabolism, Oncogene Proteins, Fusion metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Promoter Regions, Genetic genetics, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors metabolism, Transcriptional Activation, Tumor Cells, Cultured, Up-Regulation, Apoptosis drug effects, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 19 genetics, DNA-Binding Proteins genetics, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand genetics, TNF-Related Apoptosis-Inducing Ligand pharmacology, Transcription Factors genetics, Translocation, Genetic genetics
- 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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