Whole transcriptome sequencing identified a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP
- Maoxiang Qian1,
- Hui Zhang1,
- Shirley Kow-Yin Kham2,
- Shuguang Liu3,
- Chuang Jiang4,
- Xujie Zhao1,
- Yi Lu2,
- Charnise Goodings1,
- Ting-Nien Lin1,
- Ranran Zhang5,
- Takaya Moriyama1,
- Zhaohong Yin1,
- Zhenhua Li2,
- Thuan Chong Quah2,
- Hany Ariffin6,
- Ah Moy Tan7,
- Shuhong Shen8,
- Deepa Bhojwani9,
- Shaoyan Hu10,
- Suning Chen11,
- Huyong Zheng3,
- Ching-Hon Pui1,
- Allen Eng-Juh Yeoh2 and
- Jun J Yang1,12
- 1 St. Jude Children's Research Hospital;
- 2 National University of Singapore;
- 3 Beijing Children's Hospital;
- 4 Shanghai Jiao Tong University;
- 5 Guangzhou Medical University;
- 6 University of Malaya Medical Centre;
- 7 KK Women's and Children's Hospital;
- 8 Shanghai Jiao Tong University School of Medicine;
- 9 Children's Hospital of Los Angeles;
- 10 Children's Hospital of Soochow University;
- 11 First Affiliated Hospital of Soochow University
- ↵* Corresponding author; email: jun.yang{at}stjude.org
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 upregulation of CLCF1 and BTLA expression, and ZNF384 fusion proteins consistently showed higher activity to promote transcription of these target genes relative to wildtype 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 recurrent translocations involving EP300 and CREBBP may cause epigenetic deregulation with potentials for therapeutic targeting.
- Received May 1, 2016.
- Accepted November 29, 2016.
- Published by Cold Spring Harbor Laboratory Press
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