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

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.

Authors

Institutions

Publication Details

Journal
Blood
Published
2025-08-14
DOI
https://doi.org/10.1182/blood.2025028674
Citations
2
Primary Topic
Retinoids in leukemia and cellular processes
Type
article
Field-Weighted Citation Impact
1.61
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Xue‐Qun Luo, Yan‐Lai Tang, Shuqin Yan, Jianhong Zhao et al.
2 citations
Blood
Retinoids in leukemia and cellular processes
1.61
article

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

Xue‐Qun Luo, Yan‐Lai Tang, Shuqin Yan, Jianhong Zhao, Yangyang Xie, Panxiang Cao, Haibo Sun, Suning Chen, Deyan Liu, Shuhong Shen, Xian Zhang, Yue Lü, Xiaoli Ma, Fang Xu, Wenning Xu, Gaowei Fan, Jiacheng Lou, Jiancheng Fang, Libin Huang, Danna Lin, Qisheng Wu, Kun Yang, Min Xiong, Linya Wang, Ping Wu, Zhanglin Zhang, Xiaosu Zhou, Huyong Zheng, Fang Wang, Yang Wang, Hongwei Chen, Jing Li, Jing Zhang, Ming Liu, Yang Zhang, Lina Zhang, Li Chen, Siyuan Liu, Xue Chen, Li Xu, Yajie Zhang, Jiaqi Chen, Lei Wang, Tong Wang, Xiujuan Ma, Junmin Li, Hua Nan, Zhong Fan, Lihua Yang, Yan Dai, Min Zhang, Peihua Lu, Futian Ma, Xia Xiao, Yanli Zhao, Lili Yuan, Kankan Wang, Chengcheng Yan, Nan Zhang, Fanyong Lyu, Qi-Hui Chen, Jianfeng Zhou, Bing Liu, Ruijie Tang, Junfang Yang, Lijun Wen, Zhixu He, Yu Luo, Huan Du
article en
2 citations

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.

BloodVol. 146(18)
Hebei Medical University (CN), Beijing Institute of Petrochemical Technology (CN), Nanchang University (CN), Guiyang Medical University (CN), Sun Yat-sen University (CN), Shanghai Jiao Tong University (CN), Capital Medical University (CN), Dalian Medical University (CN), Sichuan University (CN), Tianjin First Center Hospital (CN), Beijing Chao-Yang Hospital, Capital Medical University (CN), Ruijin Hospital (CN), Zhengzhou University (CN), Soochow University (CN), Institute for Transfusion Medicine (US), West China Hospital of Sichuan University (CN), Hospital of Hebei Province (CN), Shanghai Children's Medical Center (CN), First Affiliated Hospital of Jiangxi Medical College (CN), Novogene Bioinformatics Institute (CN), Second Hospital of Hebei Medical University (CN), Second Affiliated Hospital of Dalian Medical University (CN), First People's Hospital of Foshan (CN), Kingmed Diagnostics (CN), Affiliated Hospital of Guizhou Medical University (CN), The People's Hospital of Guangxi Zhuang Autonomous Region (CN), Precision for Medicine (United States) (US), Zhujiang Hospital (CN), Hebei University of Chinese Medicine (CN), Suzhou Research Institute (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Annoroad Gene Technology (China) (CN), Luye Pharma (China) (CN), Beijing Dao Pei Hospital (CN), Henan Cancer Hospital (CN), Beijing Children’s Hospital (CN), Shanghai Institute of Hematology (CN), Ministry of Education (BD), Zigong First People's Hospital (CN), First Affiliated Hospital of Soochow University (CN), First Affiliated Hospital of Nanchang University (CN), First Hospital of Qinhuangdao (CN), Tianjin Medical University (CN), Southern Medical University (CN)
Good health and well-being
Openalex Percentile: Top 15%
Retinoids in leukemia and cellular processes
1.61
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.