Critical role of tripartite fusion and LBD truncation in certain RARA- and all RARG-related atypical APL

• Published in: Blood Vol. 144; no. 14; pp. 1471 - 1485
• Main Authors: Zhou, Xiaosu, Chen, Xue, Chen, Jiaqi, Wen, Lijun, Zhang, Zhanglin, Qin, Ya-Zhen, Cao, Panxiang, Xing, Haizhou, Mi, Yingchang, Wang, Wei, Zhang, Guangsen, Li, Ji, Wu, Huanling, Zhang, Zhifen, Zhang, Jian, Su, Zhan, Wang, Fang, Zhang, Yang, Ma, Xiaoli, Fang, Jiancheng, Wu, Ping, Wang, Tong, Fan, Gaowei, Zhao, Yang, Jin, David, Zhang, Xian, Ma, Xiujuan, Wu, Qisheng, Zhang, Zhihua, Wang, Linya, Ma, Futian, Xiao, Xia, Wu, Chengye, Sun, Kai, Tang, Ruijie, Zhang, Yun, Wu, Sanyun, Gao, Ran, Zhang, Leping, Zheng, Huyong, Zhao, Yanli, Zhu, Hong-Hu, Lu, Daopei, Lu, Peihua, Chen, Suning, Liu, Hongxing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.10.2024
• Subjects: Female; Humans; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - metabolism; Leukemia, Promyelocytic, Acute - pathology; Male; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Retinoic Acid Receptor alpha - genetics; Retinoic Acid Receptor alpha - metabolism; Retinoic Acid Receptor gamma; Tretinoin - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2024023883

•A novel form of X::RAR::X– or X::RAR::Y–type tripartite fusion was identified in certain RARA- and all RARG-related atypical APL.•Tripartite fusion leads to LBD-H11_12/H12 truncation of the chimeric RAR protein, rendering ATRA unresponsiveness in atypical APL. [Display omitted] Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene–positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X– or X::RAR::Y–type tripartite fusions in certain RARA-aAPL and all RARG-aAPL cases, with shared features and notable differences between these 2 disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3′ splices was associated with their 5′ fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3′ splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5′ splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3′ fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion–positive aAPL, through a protein allosteric dysfunction mechanism. Atypical acute promyelocytic leukemias (aAPLs) arise because of rare fusions between 1 of the 3 retinoic acid receptor genes (alpha [RARA], beta, and gamma [RARG]) with various partners and are usually clinically resistant to all-trans retinoic acid (ATRA) therapy. In this Plenary Paper, Zhou and colleagues provide a molecular explanation for this resistance, revealing that all RARG and some RARA fusions involve 3 rather than 2 genes, with consequent loss of the ATRA-responsive transactivation domain. These discoveries simplify identification of aAPL cases where ineffective use of ATRA can be avoided soon after diagnosis.