title: Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.
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.
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jinghui
authors: J
authors: Zhang
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Kelly
authors: 0000-0001-7868-3049
authors: K
authors: McCastlain
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Hiroki
authors: H
authors: Yoshihara
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Beisi
authors: 0000-0003-0099-858X
authors: B
authors: Xu
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Yunchao
authors: Y
authors: Chang
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Michelle L
authors: ML
authors: Churchman
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Gang
authors: 0000-0002-1678-5864
authors: G
authors: Wu
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Yongjin
authors: Y
authors: Li
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Lei
authors: L
authors: Wei
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Ilaria
authors: I
authors: Iacobucci
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Yu
authors: Y
authors: Liu
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Chunxu
authors: C
authors: Qu
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Ji
authors: J
authors: Wen
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Michael
authors: M
authors: Edmonson
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Debbie
authors: D
authors: Payne-Turner
authors: Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: Kerstin B
authors: KB
authors: Kaufmann
authors: Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|Oncology Research Laboratories, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan.
authors: Shin-Ichiro
authors: SI
authors: Takayanagi
authors: Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: Erno
authors: E
authors: Wienholds
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Human Genetics, Radboud University Medical Center and Radboud Center for Molecular Life Sciences, Nijmegen, the Netherlands.
authors: Esmé
authors: 0000-0002-2466-953X
authors: E
authors: Waanders
authors: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors: Panagiotis
authors: P
authors: Ntziachristos
authors: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors: Sofia
authors: S
authors: Bakogianni
authors: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors: Jingjing
authors: J
authors: Wang
authors: Department of Pathology, New York University School of Medicine, New York, New York, USA.|Howard Hughes Medical Institute, New York, New York, USA.
authors: Iannis
authors: I
authors: Aifantis
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Kathryn G
authors: KG
authors: Roberts
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jing
authors: J
authors: Ma
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Guangchun
authors: G
authors: Song
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: John
authors: J
authors: Easton
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Heather L
authors: HL
authors: Mulder
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Xiang
authors: X
authors: Chen
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Scott
authors: S
authors: Newman
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Xiaotu
authors: X
authors: Ma
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Michael
authors: 0000-0002-5363-1848
authors: M
authors: Rusch
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Pankaj
authors: P
authors: Gupta
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Kristy
authors: K
authors: Boggs
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Bhavin
authors: B
authors: Vadodaria
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: James
authors: J
authors: Dalton
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Yanling
authors: Y
authors: Liu
authors: Cytogenetics Core Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Marcus L
authors: ML
authors: Valentine
authors: McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
authors: Li
authors: 0000-0003-1517-2975
authors: L
authors: Ding
authors: McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
authors: Charles
authors: C
authors: Lu
authors: McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
authors: Robert S
authors: RS
authors: Fulton
authors: McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
authors: Lucinda
authors: L
authors: Fulton
authors: McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
authors: Yashodhan
authors: Y
authors: Tabib
authors: McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
authors: Kerri
authors: K
authors: Ochoa
authors: Department of Biostatistics, Colleges of Medicine, Public Health and Health Profession, University of Florida, Gainesville, Florida, USA.
authors: Meenakshi
authors: M
authors: Devidas
authors: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Deqing
authors: D
authors: Pei
authors: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Cheng
authors: C
authors: Cheng
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jun
authors: 0000-0002-0770-9659
authors: J
authors: Yang
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: William E
authors: WE
authors: Evans
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Mary V
authors: MV
authors: Relling
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Ching-Hon
authors: CH
authors: Pui
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Sima
authors: S
authors: Jeha
authors: Department of Pathology, Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, USA.
authors: Richard C
authors: RC
authors: Harvey
authors: Department of Pathology, Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, USA.
authors: I-Ming L
authors: IL
authors: Chen
authors: Department of Pathology, Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, USA.
authors: Cheryl L
authors: CL
authors: Willman
authors: Department of Hematology and Hematopoietic Cell Transplantation, Gehr Leukemia Center, City of Hope, Duarte, California, USA.
authors: Guido
authors: G
authors: Marcucci
authors: Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Clara D
authors: CD
authors: Bloomfield
authors: Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Jessica
authors: J
authors: Kohlschmidt
authors: Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Krzysztof
authors: K
authors: Mrózek
authors: Cancer Center, Montefiore Medical Center North Division, Bronx, New York, USA.
authors: Elisabeth
authors: E
authors: Paietta
authors: Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors: Martin S
authors: MS
authors: Tallman
authors: Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois, USA.
authors: Wendy
authors: W
authors: Stock
authors: Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Matthew C
authors: MC
authors: Foster
authors: Department of Medicine (Oncology), Albert Einstein College of Medicine, Montefiore Medical Center, New York, New York, USA.
authors: Janis
authors: J
authors: Racevskis
authors: Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors: Jacob M
authors: JM
authors: Rowe
authors: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Selina
authors: S
authors: Luger
authors: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Steven M
authors: SM
authors: Kornblau
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Sheila A
authors: SA
authors: Shurtleff
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Susana C
authors: SC
authors: Raimondi
authors: McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
authors: Elaine R
authors: ER
authors: Mardis
authors: McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
authors: Richard K
authors: RK
authors: Wilson
authors: Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: John E
authors: 0000-0002-9527-8317
authors: JE
authors: Dick
authors: Department of Pediatrics, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Stephen P
authors: SP
authors: Hunger
authors: Department of Pediatrics, Benioff Children's Hospital, University of California at San Francisco, San Francisco, California, USA.
authors: Mignon L
authors: ML
authors: Loh
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: James R
authors: JR
authors: Downing
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Charles G
authors: 0000-0002-1871-1850
authors: CG
authors: Mullighan
mesh_terms: D000293:Adolescent; D000328:Adult; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms; D000071230:Transcriptional Regulator ERG / Q000235:genetics; D055815:Young Adult
chemical_list: C121257:DUX4L1 protein, human; C072312:ERG protein, human; D018398:Homeodomain Proteins; D020033:Protein Isoforms; D000071230:Transcriptional Regulator ERG