TY  - JOUR
A1  - Qian, Maoxiang
A1  - Zhang, Hui
A1  - Kham, Shirley Kow-Yin
A1  - Liu, Shuguang
A1  - Jiang, Chuang
A1  - Zhao, Xujie
A1  - Lu, Yi
A1  - Goodings, Charnise
A1  - Lin, Ting-Nien
A1  - Zhang, Ranran
A1  - Moriyama, Takaya
A1  - Yin, Zhaohong
A1  - Li, Zhenhua
A1  - Quah, Thuan Chong
A1  - Ariffin, Hany
A1  - Tan, Ah Moy
A1  - Shen, Shuhong
A1  - Bhojwani, Deepa
A1  - Hu, Shaoyan
A1  - Chen, Suning
A1  - Zheng, Huyong
A1  - Pui, Ching-Hon
A1  - Yeoh, Allen Eng-Juh
A1  - Yang, Jun J.
T1  - Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP
Y1  - 2017/02/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 185 
EP  - 195 
DO  - 10.1101/gr.209163.116 
VL  - 27 
IS  - 2 
UR  - http://genome.cshlp.org/content/27/2/185.abstract 
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. 
ER  -