title: Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia.
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.affiliation: 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.
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Bai-Yan
authors.initials: BY
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jin-Yan
authors.initials: JY
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Ben-Shang
authors.initials: BS
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Lu
authors.initials: L
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Dai
authors.affiliation: Key Laboratory of Ministry of Education for Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Zi-Guan
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Kong
authors.affiliation: 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Xiang-Qin
authors.initials: XQ
authors.lastname: Weng
authors.affiliation: 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.
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hematology, First Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Department of Hematology, First Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematology, Tang Du Hospital affiliated to the Fourth Military Medical University, Xi'an, Shaan Xi 710038, China.
authors.forename: Ying-Min
authors.initials: YM
authors.lastname: Liang
authors.affiliation: Department of Hematology, Tang Du Hospital affiliated to the Fourth Military Medical University, Xi'an, Shaan Xi 710038, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Hematology, Xi Jing Hospital affiliated to the Fourth Military Medical University, Xi'an, Shaan Xi 710032, China.
authors.forename: Xie-Qun
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaan Xi 710004, China.
authors.forename: Wang-Gang
authors.initials: WG
authors.lastname: Zhang
authors.affiliation: Dalian Key Laboratory of Hematology, Department of Hematology, Second Hospital of Dalian Medical University, Dalian, Liaoning 116027, China.
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Yan
authors.affiliation: Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, China.
authors.forename: Jian-Da
authors.initials: JD
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Gu
authors.affiliation: Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.affiliation: Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Rui-Bao
authors.initials: RB
authors.lastname: Ren
authors.affiliation: Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Kan-Kan
authors.initials: KK
authors.lastname: Wang
authors.affiliation: Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.
authors.forename: Sheng-Yue
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Mi
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: 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.
authors.forename: Jing-Yan
authors.initials: JY
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D059467:Transcriptome; D055815:Young Adult
chemical_list: D015514:Oncogene Proteins, Fusion
keywords: Adult B-ALL; MEF2D fusions; Next-generation sequencing; Pediatric B-ALL; ZNF384 fusions