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Nat Genet. 2016 Dec;48(12):1481-1489. doi: 10.1038/ng.3691. Epub 2016 Oct 24.

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

Author information

1
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
2
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
3
Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
4
Oncology Research Laboratories, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan.
5
Department of Human Genetics, Radboud University Medical Center and Radboud Center for Molecular Life Sciences, Nijmegen, the Netherlands.
6
Department of Pathology, New York University School of Medicine, New York, New York, USA.
7
Howard Hughes Medical Institute, New York, New York, USA.
8
Cytogenetics Core Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
9
McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
10
Department of Biostatistics, Colleges of Medicine, Public Health and Health Profession, University of Florida, Gainesville, Florida, USA.
11
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
12
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
13
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
14
Department of Pathology, Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, USA.
15
Department of Hematology and Hematopoietic Cell Transplantation, Gehr Leukemia Center, City of Hope, Duarte, California, USA.
16
Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
17
Cancer Center, Montefiore Medical Center North Division, Bronx, New York, USA.
18
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
19
Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois, USA.
20
Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
21
Department of Medicine (Oncology), Albert Einstein College of Medicine, Montefiore Medical Center, New York, New York, USA.
22
Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.
23
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
24
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
25
Department of Pediatrics, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
26
Department of Pediatrics, Benioff Children's Hospital, University of California at San Francisco, San Francisco, California, USA.

Abstract

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.

PMID:
27776115
PMCID:
PMC5144107
DOI:
10.1038/ng.3691
[Indexed for MEDLINE]
Free PMC Article

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