1. A novel fusion protein TBLR1-RARα acts as an oncogene to induce murine promyelocytic leukemia: identification and treatment strategies
- Author
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Min Wang, Shouyun Li, Qing Rao, Kejing Tang, Zheng Tian, Yirui Chen, Xue Yang, Shuang Liu, Jianxiang Wang, Yingxi Xu, and Haiyan Xing
- Subjects
Male ,Acute promyelocytic leukemia ,Cancer Research ,Oncogene Proteins, Fusion ,Cellular differentiation ,Immunology ,Receptors, Cytoplasmic and Nuclear ,Antineoplastic Agents ,Biology ,Article ,Acute myeloid leukaemia ,Fusion gene ,Mice ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,immune system diseases ,medicine ,Animals ,Humans ,Arsenic trioxide ,neoplasms ,Cells, Cultured ,Oncogene ,QH573-671 ,Retinoic Acid Receptor alpha ,Cell Differentiation ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,Fusion protein ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,Repressor Proteins ,Haematopoiesis ,Leukemia ,Cell Transformation, Neoplastic ,HEK293 Cells ,chemistry ,Cancer research ,Female ,Cytology - Abstract
Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARα and its fusion partners. For decades, the advent of all-trans retinoic acid (ATRA) synergized with arsenic trioxide (As2O3) has turned most APL from highly fatal to highly curable. TBLR1-RARα (TR) is the tenth fusion gene of APL identified in our previous study, with its oncogenic role in the pathogenesis of APL not wholly unraveled. In this study, we found the expression of TR in mouse hematopoietic progenitors induces blockade of differentiation with enhanced proliferative capacity in vitro. A novel murine transplantable leukemia model was then established by expressing TR fusion gene in lineage-negative bone marrow mononuclear cells. Characteristics of primary TR mice revealed a rapid onset of aggressive leukemia with bleeding diathesis, which recapitulates human APL more accurately than other models. Despite the in vitro sensitivity to ATRA-induced cell differentiation, neither ATRA monotherapy nor combination with As2O3 confers survival benefit to TR mice, consistent with poor clinical outcome of APL patients with TR fusion gene. Based on histone deacetylation phenotypes implied by bioinformatic analysis, HDAC inhibitors demonstrated significant survival superiority in the survival of TR mice, yielding insights into clinical efficacy against rare types of APL.
- Published
- 2021