Tracing back of relapse clones by Ig/TCR gene rearrangements reveals complex patterns of recurrence in pediatric acute lymphoblastic leukemia
Ming-Zhu Jia
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorWei-Jing Li
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorChan-Juan Wang
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
National Key Discipline of Pediatrics, Capital Medical University, Beijing, China
Search for more papers by this authorQing Zhang
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorChao Gao
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorXiao-Tong Huang
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorTing Zhu
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorCorresponding Author
Rui-Dong Zhang
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
National Key Discipline of Pediatrics, Capital Medical University, Beijing, China
Correspondence
Rui-Dong Zhang, Hematology Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Lei Cui and Zhi-Gang Li, Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Lei Cui
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Correspondence
Rui-Dong Zhang, Hematology Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Lei Cui and Zhi-Gang Li, Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Zhi-Gang Li
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Correspondence
Rui-Dong Zhang, Hematology Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Lei Cui and Zhi-Gang Li, Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]; [email protected]
Search for more papers by this authorMing-Zhu Jia
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorWei-Jing Li
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorChan-Juan Wang
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
National Key Discipline of Pediatrics, Capital Medical University, Beijing, China
Search for more papers by this authorQing Zhang
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorChao Gao
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorXiao-Tong Huang
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorTing Zhu
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Search for more papers by this authorCorresponding Author
Rui-Dong Zhang
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
National Key Discipline of Pediatrics, Capital Medical University, Beijing, China
Correspondence
Rui-Dong Zhang, Hematology Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Lei Cui and Zhi-Gang Li, Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Lei Cui
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Correspondence
Rui-Dong Zhang, Hematology Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Lei Cui and Zhi-Gang Li, Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Zhi-Gang Li
Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
Beijing Key Laboratory of Pediatric Hematology-Oncology, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
Hematology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
Correspondence
Rui-Dong Zhang, Hematology Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]
Lei Cui and Zhi-Gang Li, Hematologic Diseases Laboratory, Beijing Pediatric Research Institute, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Email: [email protected]; [email protected]
Search for more papers by this authorMing-Zhu Jia and Wei-Jing Li contributed equally to this work.
Abstract
Introduction
Relapse remained the major obstacle to improving the prognosis of children with acute lymphoblastic leukemia (ALL). This study aimed to investigate the changing patterns of Ig/TCR gene rearrangements between diagnosis and relapse and the clinical relevance and to explore the mechanism of leukemic relapse.
Methods
Clonal Ig/TCR gene rearrangements were screened by multiplex PCR amplification in 85 paired diagnostic and relapse bone marrow (BM) samples from children with ALL. The new rearrangements presented at relapse were quantitatively assessed by the RQ-PCR approach targeting the patient-specific junctional region sequence in 19 diagnostic samples. The relapse clones were further back-traced to diagnostic and follow-up BM samples from 12 patients.
Results
Comparison of Ig/TCR gene rearrangements between diagnosis and relapse showed that 40 (57.1%) B-ALL and 5 (33.3%) T-ALL patients exhibited a change from diagnosis to relapse, and 25 (35.7%) B-ALL patients acquired new rearrangements at relapse. The new relapse rearrangements were present in 15 of the 19 (78.9%) diagnostic samples as shown by RQ-PCR, with a median level of 5.26 × 10−2. The levels of minor rearrangements correlated with B immunophenotype, WBC counts, age at diagnosis, and recurrence time. Furthermore, back-tracing rearrangements in 12 patients identified three patterns of relapse clone dynamics, which suggested the recurrence mechanisms not only through clonal selection of pre-existing subclones but also through an ongoing clonal evolution during remission and relapse.
Conclusion
Backtracking Ig/TCR gene rearrangements in relapse clones of pediatric ALL revealed complex patterns of clonal selection and evolution for leukemic relapse.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ijlh14100-sup-0001-Supinfo.docxWord 2007 document , 77.2 KB | Supplementary Table S1 Correlation between clinical characteristics and relapse of patients with acute lymphoblastic leukemia. Supplementary Table S2 Comparison of clinical characteristics in acute lymphoblastic leukemia patients with bone marrow relapse included or excluded in this study. Supplementary Table S3 The Ig/TCR gene rearrangements detected in the 85 paired diagnosis and subsequent relapse samples from pediatric ALL patients using BIOMED-2 multiplex PCR method. Supplementary Table S4 Clonality analysis of Ig/TCR gene rearrangements in 85 enrolled patients with ALL at diagnosis. Supplementary Table S5 The correlation between the quantitative levels of the “new” relapse rearrangements at diagnosis and clinical characteristics of patients. Supplementary Table S6 The quantitative levels of diagnostic and relapse rearrangements detected in the 12 patients. Supplementary Figure S1 Flow chart of this study. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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