{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:58:58Z","timestamp":1793055538505,"version":"4.5.0"},"reference-count":51,"publisher":"American Society of Hematology","issue":"18","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,30]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Integration of torque teno mini virus (TTMV) generating the TTMV::RARA (retinoic acid receptor \u03b1) 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)\u2013resistant 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025028674","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T21:17:01Z","timestamp":1755206221000},"page":"2229-2243","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":5,"title":["Epidemiology, clinical features, and molecular basis of\n                    <i>TTMV<\/i>\n                    ::\n                    <i>RARA<\/i>\n                    -driven acute promyelocytic leukemia"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9220-0442","authenticated-orcid":false,"given":"Xiaosu","family":"Zhou","sequence":"first","affiliation":[{"name":"1Precision Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China"},{"name":"2Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China"},{"name":"3Division of Pathology and Laboratory Medicine, Beijing Lu Daopei Hospital, Beijing, China"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0252-7987","authenticated-orcid":false,"given":"Jiaqi","family":"Chen","sequence":"additional","affiliation":[{"name":"1Precision Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China"},{"name":"2Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2649-5270","authenticated-orcid":false,"given":"Yan-Lai","family":"Tang","sequence":"additional","affiliation":[{"name":"5Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Sun","sequence":"additional","affiliation":[{"name":"6Bioinformatics Center, Beijing Gene Profile Research Institute, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihui","family":"Chen","sequence":"additional","affiliation":[{"name":"6Bioinformatics Center, Beijing Gene Profile Research Institute, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1282-3405","authenticated-orcid":false,"given":"Xue","family":"Chen","sequence":"additional","affiliation":[{"name":"1Precision Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China"},{"name":"2Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Precision Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China"},{"name":"2Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiancheng","family":"Fang","sequence":"additional","affiliation":[{"name":"2Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6432-1773","authenticated-orcid":false,"given":"Panxiang","family":"Cao","sequence":"additional","affiliation":[{"name":"2Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Ma","sequence":"additional","affiliation":[{"name":"2Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4464-6383","authenticated-orcid":false,"given":"Li","family":"Chen","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1606-3585","authenticated-orcid":false,"given":"Yangyang","family":"Xie","sequence":"additional","affiliation":[{"name":"8Department of Hematology, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Wen","sequence":"additional","affiliation":[{"name":"9National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8123-0235","authenticated-orcid":false,"given":"Li-Bin","family":"Huang","sequence":"additional","affiliation":[{"name":"5Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2632-011X","authenticated-orcid":false,"given":"Zhong","family":"Fan","sequence":"additional","affiliation":[{"name":"5Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3109-7266","authenticated-orcid":false,"given":"Jiacheng","family":"Lou","sequence":"additional","affiliation":[{"name":"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"},{"name":"10Department of Neurosurgery, Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Second Hospital of Dalian Medical University, Dalian, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenning","family":"Xu","sequence":"additional","affiliation":[{"name":"11Department of Hematology and Lymphoma, The First People's Hospital of Foshan, Foshan, 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The People\u2019s Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Du","sequence":"additional","affiliation":[{"name":"16Department of Hematology, Hebei Children\u2019s Hospital, Shijiazhuang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8619-9676","authenticated-orcid":false,"given":"Kun","family":"Yang","sequence":"additional","affiliation":[{"name":"17Department of Hematology, West China Hospital, Sichuan University, Chengdu, China"},{"name":"18Department of Hematology, Zigong First People's Hospital, Zigong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixu","family":"He","sequence":"additional","affiliation":[{"name":"19Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang, China"},{"name":"20Tissue Engineering and Stem Cell Experiment 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7862-6951","authenticated-orcid":false,"given":"Bing","family":"Liu","sequence":"additional","affiliation":[{"name":"22Department of Clinical Laboratory, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9257-5757","authenticated-orcid":false,"given":"Danna","family":"Lin","sequence":"additional","affiliation":[{"name":"23Department of Pediatric Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3194-3132","authenticated-orcid":false,"given":"Yajie","family":"Zhang","sequence":"additional","affiliation":[{"name":"23Department of Pediatric Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 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