title: Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors.
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.
authors: Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
authors: X
authors: X
authors: Zhang
authors: T
authors: T
authors: Inukai
authors: K
authors: K
authors: Hirose
authors: K
authors: K
authors: Akahane
authors: I
authors: I
authors: Kuroda
authors: H
authors: H
authors: Honna-Oshiro
authors: K
authors: K
authors: Kagami
authors: K
authors: K
authors: Goi
authors: K
authors: K
authors: Nakamura
authors: M
authors: M
authors: Kobayashi
authors: M
authors: M
authors: Endo
authors: H
authors: H
authors: Yagita
authors: H
authors: H
authors: Kurosawa
authors: A
authors: A
authors: Thomas Look
authors: H
authors: H
authors: Honda
authors: T
authors: T
authors: Inaba
authors: S
authors: S
authors: Nakazawa
authors: K
authors: K
authors: Sugita
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C076554:E2a-Hlf fusion protein, human; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D008156:Luciferases