Epidemiology, clinical features, and molecular basis of TTMV :: RARA -driven acute promyelocytic leukemia

作者：Xiaosu Zhou, Jiaqi Chen, Yan‐Lai Tang, Haibo Sun, Qi-Hui Chen, Xue Chen, Yang Zhang, Jiancheng Fang, Panxiang Cao, Xiaoli Ma, Li Chen, Yangyang Xie, Lijun Wen, Libin Huang, Zhong Fan, Jiacheng Lou, Wenning Xu, Nan Zhang, Jing Li, Yu Luo, Yan Dai, Huan Du, Kun Yang, Zhixu He, Xiaoyan Yang, Linya Wang, Bing Liu, Danna Lin, Yajie Zhang, Fang Xu, Min Zhang, Yang Wang, Shuqin Yan, Hua Nan, Jing Zhang, Li Xu, Xiujuan Ma, Ruijie Tang, Fang Wang, Lili Yuan, Ming Liu, Lei Wang, Qisheng Wu, Lina Zhang, Siyuan Liu, Chengcheng Yan, Jianfeng Zhou, Fanyong Lyu, Ping Wu, Tong Wang, Xian Zhang, Yue Lü, Deyan Liu, Junfang Yang, Min Xiong, Yanli Zhao, Gaowei Fan, Xia Xiao, Futian Ma, Lihua Yang, Xue‐Qun Luo, Junmin Li, Shuhong Shen, Huyong Zheng, Suning Chen, Hongwei Chen, Jianhong Zhao, Zhanglin Zhang, Kankan Wang, Peihua Lu, Hongxing Liu · 发表于：Blood · 年份：2025 · DOI：10.1182/blood.2025028674 · 被引用次数：5 · 研究领域：Retinoids in leukemia and cellular processes、Protein Degradation and Inhibitors、Virus-based gene therapy research

ABSTRACT: Integration of torque teno mini virus (TTMV) generating the TTMV::RARA (retinoic acid receptor α) fusion represents a newly recognized subtype of acute promyelocytic leukemia (APL) that merits detailed investigation. We present, to our knowledge, the first comprehensive characterization of its epidemiologic profile, clinical presentation, virologic characteristics, and underlying molecular mechanisms. Our findings indicate that TTMV::RARA is more prevalent in pediatric patients and represents the second most common retinoic acid receptor fusion after PML::RARA. Affected patients exhibit a high incidence of extramedullary involvement, particularly myeloid sarcoma. Cytogenetic abnormalities involving i(17)(q10) or 7q22 were identified in 52.0% of cases, largely in a mutually exclusive manner. Co-occurring mutations in epigenetic regulators were present in 76.9% of patients. Although most patients achieved initial remission, relapse was common and associated with rapid acquisition of all-trans retinoic acid (ATRA)-resistant mutation and secondary chemoresistance. Venetoclax-containing regimens demonstrated encouraging clinical efficacy. Phylogenetic analysis indicated that patient-derived TTMV strains clustered into a distinct clade. TTMV integration consistently occurred within RARA intron 2, involving a consensus fragment of 510 to 610 base pairs encompassing the viral promoter and open reading frame 2 (ORF2) N terminus, likely mediated by microhomology-driven recomb...