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Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors.
- Source :
-
Leukemia [Leukemia] 2012 Dec; Vol. 26 (12), pp. 2483-93. Date of Electronic Publication: 2012 May 30. - Publication Year :
- 2012
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 26
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 22743623
- Full Text :
- https://doi.org/10.1038/leu.2012.139