TBLR1 fuses to retinoid acid receptor α in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia.
The majority of acute promyelocytic leukemia (APL) cases are characterized by the PML-RARα fusion gene. Although the PML-RARα fusion gene can be detected in >98% of APL cases, RARα is also found to be fused with other partner genes, which are also related to all-trans retinoic acid (ATRA)-dependent transcriptional activity and cell differentiation. In this study, we identified a novel RARα fusion gene, TBLR1-RARα (GenBank KF589333), in a rare case of APL with a t(3;17)(q26;q21),t(7;17)(q11.2;q21) complex chromosomal rearrangement. To our knowledge, TBLR1-RARα is the 10th RARα chimeric gene that has been reported up to now. TBLR1-RARα contained the B-F domains of RARα and exhibited a distinct subcellular localization. It could form homodimers and also heterodimers with retinoid X receptor α. As a result, TBLR1-RARα exhibited diminished transcriptional activity by recruitment of more transcriptional corepressors compared with RARα. In the presence of pharmacologic doses of ATRA, TBLR1-RARα could be degraded, and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RARα could mediate the dissociation and degradation of transcriptional corepressors, consequent transactivation of RARα target genes, and cell differentiation induction in a dose- and time-dependent manner.
State Key Laboratory of Experimental Hematology.
Yirui
Y
Chen
State Key Laboratory of Experimental Hematology.
Shouyun
S
Li
Department of Clinical Hematology, and.
Chunlin
C
Zhou
Department of Hematopathology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; and.
Chengwen
C
Li
Department of Hematopathology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; and.
Kun
K
Ru
State Key Laboratory of Experimental Hematology.
Qing
Q
Rao
State Key Laboratory of Experimental Hematology.
Haiyan
H
Xing
State Key Laboratory of Experimental Hematology.
Zheng
Z
Tian
State Key Laboratory of Experimental Hematology.
Kejing
K
Tang
Department of Clinical Hematology, and.
Yingchang
Y
Mi
Department of Clinical Hematology, Weifang People's Hospital, Shandong, China.
Baohong
B
Wang
State Key Laboratory of Experimental Hematology.
Min
M
Wang
State Key Laboratory of Experimental Hematology, Department of Clinical Hematology, and.
Jianxiang
J
Wang
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D003001:Cloning, Molecular; D004273:DNA, Neoplasm / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007621:Karyotyping; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055503:Protein Multimerization; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; C473691:TBL1XR1 protein, human; D015534:Trans-Activators; D014212:Tretinoin