Abstract
Identifying and targeting oncogenic fusion genes have revolutionized the treatment of leukemia, such as PML-RARα fusion gene in acute promyelocytic leukemia. Here we identified an intrachromosomal fusion gene located on chromosome 19q.13 between UBA2 and WTIP gene in a case of acute myeloid leukemia. The UBA2-WTIP fusion gene contains the N-terminal E1_enzyme_family, VAE_Ubl domains of UBA2, and the C-terminal LIM domains of WTIP. The UBA2-WTIP fusion was detected by reverse transcriptase polymerase chain reaction and Sanger sequencing in 19 of 56 acute myeloid leukemia samples (33.9%). Ectopic expression of the UBA2-WTIP fusion in human acute myeloid leukemia KG-1a cells showed enhanced cell proliferation both in vitro and in vivo. The UBA2-WTIP fusion induced phosphorylation of STAT3, STAT5 and ERK1/2, and abrogates WTIP-mediated mammalian processing body formation. Finally, triptolide displayed selective cytotoxicity against KG-1a cells harboring the UBA2-WTIP fusion. Collectively, our findings suggest that the UBA2-WTIP fusion is an oncogenic fusion gene, as well as a promising therapeutic target for the treatment of acute myeloid leukemia.
Keywords:
Acute myeloid leukemia; Fusion gene; UBA2; WTIP.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Alkylating / pharmacology
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Apoptosis / drug effects
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Co-Repressor Proteins
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Cytoskeletal Proteins
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Diterpenes / pharmacology
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Epoxy Compounds / pharmacology
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Gene Expression Regulation, Leukemic*
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / mortality
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Leukemia, Myeloid, Acute / pathology
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Leukocytes / drug effects
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Leukocytes / metabolism*
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Leukocytes / pathology
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Mice
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Mice, Inbred NOD
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Phenanthrenes / pharmacology
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Protein Domains
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Survival Analysis
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Ubiquitin-Activating Enzymes / genetics*
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Ubiquitin-Activating Enzymes / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Alkylating
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Carrier Proteins
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Co-Repressor Proteins
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Cytoskeletal Proteins
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Diterpenes
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Epoxy Compounds
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Oncogene Proteins, Fusion
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Phenanthrenes
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RNA, Messenger
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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UBA2 protein, human
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WTIP protein, human
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triptolide
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MAPK1 protein, human
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MAPK3 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Ubiquitin-Activating Enzymes