Epidemiology, clinical features, and molecular basis of TTMV::RARA-driven acute promyelocytic leukemia.
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Zhou Xiaosu, Chen Jiaqi, Tang Yan-Lai, Sun Haibo, Chen Qihui, Chen Xue, Zhang Yang, Fang Jiancheng, Cao Panxiang, Ma Xiaoli, Chen Li, Xie Yangyang, Wen Lijun, Huang Li-Bin, Fan Zhong, Lou Jiacheng, Xu Wenning, Zhang Nan, Li Jing, Luo Yu, Dai Yan, Du Huan, Yang Kun, He Zhixu, Yang Xiaoyan, Wang Linya, Liu Bing, Lin Danna, Zhang Yajie, Xu Fang, Zhang Min, Wang Yang, Yan Shu, Nan Hua, Zhang Jing, Xu Li, Ma Xiujuan, Tang Ruijie, Wang Fang, Yuan Lili, Liu Ming, Wang Lei, Wu Qisheng, Zhang Lina, Liu Siyuan, Yan Chengcheng, Zhou Jianfeng, Lyu Fanyong, Wu Ping, Wang Tong, Zhang Xian, Lu Yue, Liu Deyan, Yang Junfang, Xiong Min, Zhao Yanli, Fan Gaowei, Xiao Xia, Ma Futian, Yang Lihua, Luo Xue-Qun, Li Junmin, Shen Shuhong, Zheng Huyong, Chen Suning, Chen Hongwei, Zhao Jianhong, Zhang Zhanglin, Wang Kankan, Lu Peihua, Liu Hongxing
Аннотация
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 recombination. Tandem RUNX1-binding motifs within the integrated viral promoter may underlie the myelotropism of these TTMV strains and facilitate transcriptional activation of TTMV::RARA. The chimeric protein retains at least the first 56 N-terminal residues of ORF2 and remains transcriptionally responsive to pharmacological concentrations of ATRA. These findings establish TTMV::RARA-APL as a distinct leukemia entity, laying the foundation for future studies on virus-mediated leukemogenesis and therapeutic strategies.