title: Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP.
abstract: Chromosomal translocations are a genomic hallmark of many hematologic malignancies. Often as initiating events, these structural abnormalities result in fusion proteins involving transcription factors important for hematopoietic differentiation and/or signaling molecules regulating cell proliferation and cell cycle. In contrast, epigenetic regulator genes are more frequently targeted by somatic sequence mutations, possibly as secondary events to further potentiate leukemogenesis. Through comprehensive whole-transcriptome sequencing of 231 children with acute lymphoblastic leukemia (ALL), we identified 58 putative functional and predominant fusion genes in 54.1% of patients (n = 125), 31 of which have not been reported previously. In particular, we described a distinct ALL subtype with a characteristic gene expression signature predominantly driven by chromosomal rearrangements of the ZNF384 gene with histone acetyltransferases EP300 and CREBBP ZNF384-rearranged ALL showed significant up-regulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wild-type ZNF384 in vitro. Ectopic expression of EP300-ZNF384 and CREBBP-ZNF384 fusion altered differentiation of mouse hematopoietic stem and progenitor cells and also potentiated oncogenic transformation in vitro. EP300- and CREBBP-ZNF384 fusions resulted in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation and increased sensitivity of leukemia cells to histone deacetylase inhibitors. In conclusion, our results indicate that gene fusion is a common class of genomic abnormalities in childhood ALL and that recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potential for therapeutic targeting.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Maoxiang
authors.initials: M
authors.lastname: Qian
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.|Department of Pediatrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China, 510120.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599.
authors.forename: Shirley Kow-Yin
authors.initials: SK
authors.lastname: Kham
authors.affiliation: Beijing Key Laboratory of Pediatric Hematology Oncology, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China, 100045.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Liu
authors.affiliation: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China, 200240.
authors.forename: Chuang
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Xujie
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Charnise
authors.initials: C
authors.lastname: Goodings
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Ting-Nien
authors.initials: TN
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China, 510120.
authors.forename: Ranran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Takaya
authors.initials: T
authors.lastname: Moriyama
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599.|VIVA-University Children's Cancer Centre, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, 119228.
authors.forename: Thuan Chong
authors.initials: TC
authors.lastname: Quah
authors.affiliation: Paediatric Haematology-Oncology Unit, University of Malaya Medical Centre, Kuala Lumpur, Malaysia, 59100.
authors.forename: Hany
authors.initials: H
authors.lastname: Ariffin
authors.affiliation: KKH-CCF Children's Cancer Centre, Paediatric Haematology & Oncology, KK Women's and Children's Hospital, Singapore, 229899.
authors.forename: Ah Moy
authors.initials: AM
authors.lastname: Tan
authors.affiliation: Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 200127.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California 90027, USA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.affiliation: Department of Hematology & Oncology, Children's Hospital of Soochow University, Suzhou, China, 215025.
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China, 215006.
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.affiliation: Beijing Key Laboratory of Pediatric Hematology Oncology, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China, 100045.
authors.forename: Huyong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.|Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599.|VIVA-University Children's Cancer Centre, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, 119228.
authors.forename: Allen Eng-Juh
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.|Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics*; D050881:E1A-Associated p300 Protein / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D023281:Genomics; D006801:Humans; D008297:Male; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics; D000073336:Whole Genome Sequencing
chemical_list: D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; C498621:ZNF384 protein, human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human