Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors

• Published in: Leukemia Vol. 26; no. 12; pp. 2483 - 2493
• Main Authors: ZHANG, X, INUKAI, T, ENDO, M, YAGITA, H, KUROSAWA, H, THOMAS LOOK, A, HONDA, H, INABA, T, NAKAZAWA, S, SUGITA, K, HIROSE, K, AKAHANE, K, KURODA, I, HONNA-OSHIRO, H, KAGAMI, K, GOI, K, NAKAMURA, K, KOBAYASHI, M
• Format: Journal Article
• Language: English
• Published: Avenel, NJ Nature Publishing Group 01.12.2012
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Bone marrow; Cell death; Cell Proliferation; Chemoresistance; Chromosomes, Human, Pair 17 - genetics; Chromosomes, Human, Pair 19 - genetics; Cytotoxicity; Death; Death receptors; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Electrophoretic Mobility Shift Assay; Gene expression; Genetic aspects; Hematologic and hematopoietic diseases; Humans; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukemogenesis; Ligands; Luciferases - metabolism; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Medical prognosis; Medical sciences; Medicine; Mitochondria; Mortality; Natural killer cells; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncology; Patients; Pediatrics; Physiological aspects; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Promoter Regions, Genetic - genetics; Radiation; Real-Time Polymerase Chain Reaction; Receptors; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Remission; Remission (Medicine); Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Stem cell transplantation; Stem cells; T cells; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL protein; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Translocation, Genetic - genetics; Transplantation; Tumor Cells, Cultured; Tumor necrosis factor-TNF; Up-Regulation; Japan; Graft versus leukemia reaction; E2A-HLF; Hematology; Cytokine; Malignant hemopathy; Carcinogenesis; Transcription factor E2A; Tumor necrosis factor; Cell death; acute lymphoblastic leukemia; Lymphoproliferative syndrome; Death receptor; TNF related apoptosis inducing ligand; TNF-related apoptosis-inducing ligand; Acute lymphocytic leukemia; Cancer; Apoptosis; graft-versus-leukemia effect
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.139

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.