Epidemiology, clinical features, and molecular basis of <i>TTMV</i> :: <i>RARA</i> -driven acute promyelocytic leukemia
Abstract
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 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.
Article Details
Authors (71)
Xiaosu Zhou
2Beijing Lu Daopei Institute of Hematology, Beijing, China
Jiaqi Chen
Yan-Lai Tang
5Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Haibo Sun
Qihui Chen
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter
Xue Chen
Yang Zhang
Jiancheng Fang
Institute of Large-Scale Scientific Facility, School of Instrumentation Science and Opto-Electronics Engineering, Beihang University
Panxiang Cao
1Hebei Yanda Lu Daopei Hospital, Langfang, China
Xiaoli Ma
Institute of Physics, Chinese Academy of Sciences
Li Chen
YangYang Xie
Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Lijun Wen
Li-Bin Huang
Zhong Fan
1Univeristy of Texas Health Science Center at Houston, Houston, United States
Jiacheng Lou
7Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wenning Xu
11Department of Hematology and Lymphoma, The First People's Hospital of Foshan, Foshan, China
Nan Zhang
Jing Li
Yu Luo
Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences
Yan Dai
Huan Du
State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering
Kun Yang
Zhixu He
19Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang, China
Xiaoyan Yang
Linya Wang
1Peking University People's Hospital, Beijing, China
Bing Liu
Danna Lin
23Department of Pediatric Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
Yajie Zhang
Center for Carbon-Based Electronics and Key Laboratory for the Physics and Chemistry of Nanodevices, School of Electronics
Fang Xu
Key Laboratory of Optoelectronic Chemical Materials and Devices (Ministry of Education), School of Optoelectronic Materials and Technology
Min Zhang
Yang Wang
Shu Yan
Hua Nan
Jing Zhang
Li Xu
Xiujuan Ma
Ruijie Tang
Fang Wang
Lili Yuan
1Hebei Yanda Lu Daopei Hospital, Langfang, Langfang, China
Ming Liu
Lei Wang
Qisheng Wu
Lina Zhang
Siyuan Liu
Sydney Dental School, Faculty of Medicine and Health, Charles Perkins Centre
Chengcheng Yan
2Tianjin Kingmed Diagnostics Laboratory Co.Ltd, Tianjin, China., Tianjin, China
Jianfeng Zhou
Fanyong Lyu
28Department of Hematology, Beijing Lu Daopei Hospital, Beijing, China
Ping Wu
Department of Neurobiology, University of Texas Medical Branch
Tong Wang
Xian Zhang
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry
Yue Lu
Deyan Liu
1Hebei Yanda Lu Daopei Hospital, Langfang, China
Junfang Yang
1Hebei Yanda Lu Daopei Hospital, Langfang, China
Min Xiong
Yanli Zhao
School of Chemistry, Chemical Engineering and Biotechnology
Gaowei Fan
Xia Xiao
Futian Ma
16Department of Hematology, Hebei Children’s Hospital, Shijiazhuang, China
Lihua Yang
Xue-Qun Luo
5Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Junmin Li
Shuhong Shen
1Department of Hematology/Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, National Health Committee Key Laboratory of Pediatric Hematology and Oncology, Shanghai, China
Huyong Zheng
1Beijing Children's Hospital, Capital Medical University, Beijing, China
Suning Chen
Hongwei Chen
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center at Nanjing University, School of Chemistry
Jianhong Zhao
Jining No.1 People’s Hospital, Jining, China
Zhanglin Zhang
4Department of Blood Transfusion, The First Affiliated Hospital of Nanchang University, Jiangxi Key Laboratory of transfusion, Institute of Transfusion, Jiangxi Academy of Clinical Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
Kankan Wang
Peihua Lu
1Hebei Yanda Lu Daopei Hospital, Langfang, China
Hongxing Liu
1Hebei Yanda Lu Daopei Hospital, Langfang, China