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Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia.
EBioMedicine 2016; 8:173-183E

Abstract

Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.

Authors+Show Affiliations

State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China; Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaan Xi 710004, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.Key Laboratory of Pediatric Hematology & Oncology, Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.Key Laboratory of Ministry of Education for Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.Department of Hematology, First Hospital of China Medical University, Shenyang 110001, China.Department of Hematology, First Hospital of China Medical University, Shenyang 110001, China.Department of Hematology, Tang Du Hospital affiliated to the Fourth Military Medical University, Xi'an, Shaan Xi 710038, China.Department of Hematology, Tang Du Hospital affiliated to the Fourth Military Medical University, Xi'an, Shaan Xi 710038, China.Department of Hematology, Xi Jing Hospital affiliated to the Fourth Military Medical University, Xi'an, Shaan Xi 710032, China.Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaan Xi 710004, China.Dalian Key Laboratory of Hematology, Department of Hematology, Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, China.Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, China.Key Laboratory of Pediatric Hematology & Oncology, Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.Key Laboratory of Pediatric Hematology & Oncology, Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.Key Laboratory of Pediatric Hematology & Oncology, Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.Key Laboratory of Pediatric Hematology & Oncology, Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China; Key Laboratory of Ministry of Education for Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China; Key Laboratory of Ministry of Education for Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: sjchen@stn.sh.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27428428

Citation

Liu, Yuan-Fang, et al. "Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia." EBioMedicine, vol. 8, 2016, pp. 173-183.
Liu YF, Wang BY, Zhang WN, et al. Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia. EBioMedicine. 2016;8:173-183.
Liu, Y. F., Wang, B. Y., Zhang, W. N., Huang, J. Y., Li, B. S., Zhang, M., ... Chen, S. J. (2016). Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia. EBioMedicine, 8, pp. 173-183. doi:10.1016/j.ebiom.2016.04.038.
Liu YF, et al. Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia. EBioMedicine. 2016;8:173-183. PubMed PMID: 27428428.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia. AU - Liu,Yuan-Fang, AU - Wang,Bai-Yan, AU - Zhang,Wei-Na, AU - Huang,Jin-Yan, AU - Li,Ben-Shang, AU - Zhang,Ming, AU - Jiang,Lu, AU - Li,Jian-Feng, AU - Wang,Ming-Jie, AU - Dai,Yu-Jun, AU - Zhang,Zi-Guan, AU - Wang,Qiang, AU - Kong,Jie, AU - Chen,Bing, AU - Zhu,Yong-Mei, AU - Weng,Xiang-Qin, AU - Shen,Zhi-Xiang, AU - Li,Jun-Min, AU - Wang,Jin, AU - Yan,Xiao-Jing, AU - Li,Yan, AU - Liang,Ying-Min, AU - Liu,Li, AU - Chen,Xie-Qun, AU - Zhang,Wang-Gang, AU - Yan,Jin-Song, AU - Hu,Jian-Da, AU - Shen,Shu-Hong, AU - Chen,Jing, AU - Gu,Long-Jun, AU - Pei,Deqing, AU - Li,Yongjin, AU - Wu,Gang, AU - Zhou,Xin, AU - Ren,Rui-Bao, AU - Cheng,Cheng, AU - Yang,Jun J, AU - Wang,Kan-Kan, AU - Wang,Sheng-Yue, AU - Zhang,Jinghui, AU - Mi,Jian-Qing, AU - Pui,Ching-Hon, AU - Tang,Jing-Yan, AU - Chen,Zhu, AU - Chen,Sai-Juan, Y1 - 2016/05/13/ PY - 2016/02/21/received PY - 2016/04/11/revised PY - 2016/04/29/accepted PY - 2016/7/19/entrez PY - 2016/7/20/pubmed PY - 2017/2/15/medline KW - Adult B-ALL KW - MEF2D fusions KW - Next-generation sequencing KW - Pediatric B-ALL KW - ZNF384 fusions SP - 173 EP - 183 JF - EBioMedicine JO - EBioMedicine VL - 8 N2 - Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment. SN - 2352-3964 UR - https://www.unboundmedicine.com/medline/citation/27428428/Genomic_Profiling_of_Adult_and_Pediatric_B_cell_Acute_Lymphoblastic_Leukemia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-3964(16)30181-5 DB - PRIME DP - Unbound Medicine ER -