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-RAR alpha fusion gene. Although the PML-RARa fusion gene can be detected in >98% of APL cases, RAR alpha 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 RAR alpha fusion gene, TBLR1-RAR alpha(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-RARa is the 10th RARa chimeric gene that has been reported up to now. TBLR1-RAR alpha contained the B-F domains of RAR alpha and exhibited a distinct subcellular localization. It could form homodimers and also heterodimers with retinoid X receptor a. As a result, TBLR1-RARa exhibited diminished transcriptional activity by recruitment of more transcriptional corepressors compared with RARa. In the presence of pharmacologic doses of ATRA, TBLR1-RAR alpha could be degraded, and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RAR alpha could mediate the dissociation and degradation of transcriptional corepressors, consequent transactivation of RAR alpha target genes, and cell differentiation induction in a dose-and time-dependent manner.