TY - JOUR
T1 - Deregulation of DUX4 and ERG in acute lymphoblastic leukemia
AU - for the St. Jude Children's Research Hospital?Washington University Pediatric Cancer Genome Project
AU - Zhang, Jinghui
AU - McCastlain, Kelly
AU - Yoshihara, Hiroki
AU - Xu, Beisi
AU - Chang, Yunchao
AU - Churchman, Michelle L.
AU - Wu, Gang
AU - Li, Yongjin
AU - Wei, Lei
AU - Iacobucci, Ilaria
AU - Liu, Yu
AU - Qu, Chunxu
AU - Wen, Ji
AU - Edmonson, Michael
AU - Payne-Turner, Debbie
AU - Kaufmann, Kerstin B.
AU - Takayanagi, Shin Ichiro
AU - Wienholds, Erno
AU - Waanders, Esmé
AU - Ntziachristos, Panagiotis
AU - Bakogianni, Sofia
AU - Wang, Jingjing
AU - Aifantis, Iannis
AU - Roberts, Kathryn G.
AU - Ma, Jing
AU - Song, Guangchun
AU - Easton, John
AU - Mulder, Heather L.
AU - Chen, Xiang
AU - Newman, Scott
AU - Ma, Xiaotu
AU - Rusch, Michael
AU - Gupta, Pankaj
AU - Boggs, Kristy
AU - Vadodaria, Bhavin
AU - Dalton, James
AU - Liu, Yanling
AU - Valentine, Marcus L.
AU - Ding, Li
AU - Lu, Charles
AU - Fulton, Robert S.
AU - Fulton, Lucinda
AU - Tabib, Yashodhan
AU - Ochoa, Kerri
AU - Devidas, Meenakshi
AU - Pei, Deqing
AU - Cheng, Cheng
AU - Yang, Jun
AU - Evans, William E.
AU - Relling, Mary V.
N1 - Publisher Copyright:
© 2016 Nature America, Inc. part of Springer Nature, All Rights reserved.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt uses a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivation domains of ERG, but it inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia in which DUX4 deregulation results in loss of function of ERG, either by deletion or induced expression of an isoform that is a dominant-negative inhibitor of wild-type ERG function.
AB - Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt uses a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivation domains of ERG, but it inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia in which DUX4 deregulation results in loss of function of ERG, either by deletion or induced expression of an isoform that is a dominant-negative inhibitor of wild-type ERG function.
UR - http://www.scopus.com/inward/record.url?scp=84992387949&partnerID=8YFLogxK
U2 - 10.1038/ng.3691
DO - 10.1038/ng.3691
M3 - Article
C2 - 27776115
AN - SCOPUS:84992387949
SN - 1061-4036
VL - 48
SP - 1481
EP - 1489
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -