Case report of pediatric TTMV-related acute promyelocytic leukemia with central nervous system infiltration and rapid accumulation of RARA-LBD mutations
Linya Wang,
Jiaqi Chen,
Bei Hou,
Ying Wu,
Jun Yang,
Xiaosu Zhou,
Qihui Chen,
Xue Chen,
Yang Zhang,
Fang Wang,
Jiancheng Fang,
Panxiang Cao,
Mingyue Liu,
Yanan Li,
Pan Zhang,
Yan Liu,
Ruidong Zhang,
Hongxing Liu,
Huyong Zheng
Affiliations
Linya Wang
Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China
Jiaqi Chen
Molecular Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China; Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China
Bei Hou
Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China
Ying Wu
Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China
Jun Yang
Stem Cell Transplantation Department, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Clinical Discipline of Pediatric Hematology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China
Xiaosu Zhou
Molecular Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China
Qihui Chen
Precision Medicine Center, Beijing Gene Profile Research Institute, Beijing, China
Xue Chen
Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China
Yang Zhang
Molecular Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China; Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China
Fang Wang
Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China
Jiancheng Fang
Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China
Panxiang Cao
Molecular Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China; Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China
Mingyue Liu
Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China
Yanan Li
Hematology and Oncology Department, Beijing Children's Hospital Baoding Hospital, Baoding, China
Pan Zhang
Stem Cell Transplantation Department, Beijing Children's Hospital, Baoding Hospital, Capital Medical University, Baoding, China
Yan Liu
Hematology and Oncology Department, Beijing Children's Hospital Baoding Hospital, Baoding, China
Ruidong Zhang
Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China
Hongxing Liu
Molecular Medicine Center, Beijing Lu Daopei Institute of Hematology, Beijing, China; Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, China; Division of Pathology & Laboratory Medicine, Beijing Lu Daopei Hospital, Beijing, China; Department of Oncology, Capital Medical University, Beijing, China; Corresponding author. Molecular Medicine Center, Beijing Lu Daopei Institute of Hematology; Department of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital; Division of Pathology & Laboratory Medicine, Beijing Lu Daopei Hospital; Department of Oncology, Capital Medical University, 100176, China
Huyong Zheng
Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China; Corresponding author. Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China.
TTMV::RARA is a recently reported fusion gene associated with acute promyelocytic leukemia (APL), caused by the integration of torque teno mini virus (TTMV) genomic fragments into the second intron of the RARA gene. Currently, there have been only six documented cases, with clinical presentations showing significant variability. Although initial responses to all-trans retinoic acid (ATRA) treatment may be observed in patients with TTMV::RARA-APL, the overall prognosis remains unfavorable among infrequent reported cases. This article presents a pediatric case that manifested as PML::RARA-negative APL with central nervous system involvement at onset. The patient experienced both intramedullary and extramedullary relapse one year after undergoing allogeneic hematopoietic stem cell transplantation. Upon identification as TTMV::RARA-APL and subsequent administration of two rounds of ATRA-based treatment, the patient rapidly developed multiple RARA ligand-binding domain mutations and demonstrated extensive resistance to ATRA and various other therapeutic interventions. Additionally, the patient experienced ARID1A mutant clone expansion and progressed MYC-targeted gene activation. This case represents the first documentation of extramedullary involvement at both the initial diagnosis and relapse stages, emphasizing the intricate clinical features and challenges associated with the rapid accumulation of multiple ATRA-resistant mutations in TTMV::RARA-APL, characterizing it as a distinct and complex sub-entity of atypical APL.
