Tags

Type your tag names separated by a space and hit enter

Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP.
Genome Res 2017; 27(2):185-195GR

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+Show Affiliations

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.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.Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599.Beijing Key Laboratory of Pediatric Hematology Oncology, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China, 100045.School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China, 200240.Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599.Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.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.Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599.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.Paediatric Haematology-Oncology Unit, University of Malaya Medical Centre, Kuala Lumpur, Malaysia, 59100.KKH-CCF Children's Cancer Centre, Paediatric Haematology & Oncology, KK Women's and Children's Hospital, Singapore, 229899.Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 200127.Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California 90027, USA.Department of Hematology & Oncology, Children's Hospital of Soochow University, Suzhou, China, 215025.Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China, 215006.Beijing Key Laboratory of Pediatric Hematology Oncology, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China, 100045.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

27903646

Citation

Qian, Maoxiang, et al. "Whole-transcriptome Sequencing Identifies a Distinct Subtype of Acute Lymphoblastic Leukemia With Predominant Genomic Abnormalities of EP300 and CREBBP." Genome Research, vol. 27, no. 2, 2017, pp. 185-195.
Qian M, Zhang H, Kham SK, et al. Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. Genome Res. 2017;27(2):185-195.
Qian, M., Zhang, H., Kham, S. K., Liu, S., Jiang, C., Zhao, X., ... Yang, J. J. (2017). Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. Genome Research, 27(2), pp. 185-195. doi:10.1101/gr.209163.116.
Qian M, et al. Whole-transcriptome Sequencing Identifies a Distinct Subtype of Acute Lymphoblastic Leukemia With Predominant Genomic Abnormalities of EP300 and CREBBP. Genome Res. 2017;27(2):185-195. PubMed PMID: 27903646.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP. AU - Qian,Maoxiang, AU - Zhang,Hui, AU - Kham,Shirley Kow-Yin, AU - Liu,Shuguang, AU - Jiang,Chuang, AU - Zhao,Xujie, AU - Lu,Yi, AU - Goodings,Charnise, AU - Lin,Ting-Nien, AU - Zhang,Ranran, AU - Moriyama,Takaya, AU - Yin,Zhaohong, AU - Li,Zhenhua, AU - Quah,Thuan Chong, AU - Ariffin,Hany, AU - Tan,Ah Moy, AU - Shen,Shuhong, AU - Bhojwani,Deepa, AU - Hu,Shaoyan, AU - Chen,Suning, AU - Zheng,Huyong, AU - Pui,Ching-Hon, AU - Yeoh,Allen Eng-Juh, AU - Yang,Jun J, Y1 - 2016/11/30/ PY - 2016/05/01/received PY - 2016/11/29/accepted PY - 2016/12/3/pubmed PY - 2018/1/6/medline PY - 2016/12/2/entrez SP - 185 EP - 195 JF - Genome research JO - Genome Res. VL - 27 IS - 2 N2 - 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. SN - 1549-5469 UR - https://www.unboundmedicine.com/medline/citation/27903646/Whole_transcriptome_sequencing_identifies_a_distinct_subtype_of_acute_lymphoblastic_leukemia_with_predominant_genomic_abnormalities_of_EP300_and_CREBBP_ L2 - http://genome.cshlp.org/cgi/pmidlookup?view=long&pmid=27903646 DB - PRIME DP - Unbound Medicine ER -