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Epidemiology, Clinical Features, and Molecular Basis of TTMV::RARA-driven Acute Promyelocytic Leukemia

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机构: [1]Department of Oncology, Capital Medical University, China. [2]Beijing Lu Daopei Institute of Hematology, China. [3]Sun Yat-sen University, Guangzhou, China. [4]Beijing Geneprofile Research Institute, Beijing, China. [5]Beijing Geneprofile Technologies Co,.Ltd, Beijing, China. [6]Precision Medicine Center, Beijing Lu Daopei Institute of Hematology, China. [7]Hebei Yanda Lu Daopei Hospital, Langfang, China. [8]Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China. [9]Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. [10]Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Healt, Suzhou, China. [11]The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. [12]The First Affifiliated Hospital, Sun Yat-sen University, Guangzhou, China. [13]Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, shanghai, China. [14]The First People's Hospital of Foshan, Foshan, China. [15]Hebei Provincial Hospital of Chinese Medicine, Shijiazhuang, China. [16]The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, China. [17]Hebei Children's Hospital, Shijiazhuang, China. [18]Department of Hematology, Zigong First People's Hospital, China. [19]Tissue Engineering and Stem Cell Experiment Center, Guizhou Medical University, China. [20]Affiliated Hospital of Guizhou Medical University, Guiyang, China. [21]Beijing Children's Hospital, Beijing, China. [22]The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China. [23]Southern Medical University Zhujiang Hospital, Guangzhou, China. [24]Zhujiang Hospital of Southen Medical University, Guangzhou, China. [25]Beijing Lu Daopei Hospital, China. [26]Department of Hematology, Beijing Lu Daopei Hospital, China. [27]Beijing Lu Daopei Hospital, Beijing, China. [28]Division of Pathology and Laboratory Medicine, Beijing Lu Daopei Hospital, Beijing, China. [29]Beijing Lu Daopei Institute of Hematology, Beijing, China. [30]Tianjin Kingmed Diagnostics Laboratory Co.Ltd, Tianjin, China. [31]Beijing Kingmed Diagnostics Laboratory Co. Ltd, Beijing, China. [32]28Department of Hematology, Beijing Lu Daopei Hospital, Beijing, China, 100176, China. [33]Division of Pathology and Laboratory Medicine, Beijing Lu Daopei Hospital, China. [34]Department of Bone Marrow Transplantation, Beijing Lu Daopei Hospital, China. [35]Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. [36]Tianjin First Central Hospital, Tianjin, Alabama, China. [37]Hebei Children's Hospital, Shijiazhuang, Alabama, China. [38]ZhujiangZhujiang Hospital, Southern Medical University Hospital, Southern Medical University, Guangzhou, China. [39]Shanghai Ruijin Hospital, Shanghai, China. [40]Beijing Children's Hospital, Capital Medical University, Beijing, China. [41]Jiangsu institute of hematology, Suzhou, China. [42]First Hospital of Qinhuangdao, Qinhuangdao, China. [43]Hebei Medical University, China. [44]Department of transfusion, Institute of transfusion, Jiangxi Key Laboratory of transfusion, The First affiliated hospital of Nanchang university, Nanchang, China. [45]State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of, Shanghai, China. [46]Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, China.
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关键词: acute promyelocytic leukemia torque teno mini virus gene fusion

摘要:
Integration of torque teno mini virus (TTMV) generating the TTMV::RARA fusion represents a newly recognized subtype of acute promyelocytic leukemia (APL) that merits detailed investigation. We present 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 510-610 bp encompassing the viral promoter and 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.Copyright © 2025 American Society of Hematology.

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大类 | 1 区 医学
小类 | 1 区 血液学
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大类 | 1 区 医学
小类 | 1 区 血液学
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Q1 HEMATOLOGY
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Q1 HEMATOLOGY

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第一作者机构: [1]Department of Oncology, Capital Medical University, China.
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