Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP
- Maoxiang Qian1,15,
- Hui Zhang1,2,15,
- Shirley Kow-Yin Kham3,
- Shuguang Liu4,
- Chuang Jiang5,
- Xujie Zhao1,
- Yi Lu3,
- Charnise Goodings1,
- Ting-Nien Lin1,
- Ranran Zhang2,
- Takaya Moriyama1,
- Zhaohong Yin1,
- Zhenhua Li3,
- Thuan Chong Quah3,6,
- Hany Ariffin7,
- Ah Moy Tan8,
- Shuhong Shen9,
- Deepa Bhojwani10,
- Shaoyan Hu11,
- Suning Chen12,
- Huyong Zheng4,
- Ching-Hon Pui13,14,
- Allen Eng-Juh Yeoh3,6 and
- Jun J. Yang1,14
- 1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
- 2Department of Pediatrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China, 510120;
- 3Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599;
- 4Beijing Key Laboratory of Pediatric Hematology Oncology, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China, 100045;
- 5School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China, 200240;
- 6VIVA–University Children's Cancer Centre, Khoo Teck Puat–National University Children’s Medical Institute, National University Hospital, National University Health System, Singapore, 119228;
- 7Paediatric Haematology-Oncology Unit, University of Malaya Medical Centre, Kuala Lumpur, Malaysia, 59100;
- 8KKH-CCF Children's Cancer Centre, Paediatric Haematology & Oncology, KK Women's and Children's Hospital, Singapore, 229899;
- 9Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China, 200127;
- 10Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California 90027, USA;
- 11Department of Hematology & Oncology, Children's Hospital of Soochow University, Suzhou, China, 215025;
- 12Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China, 215006;
- 13Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
- 14Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
- Corresponding authors: jun.yang{at}stjude.org; allen_yeoh{at}nuhs.edu.sg
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↵15 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.209163.116.
- Received May 1, 2016.
- Accepted November 29, 2016.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
