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Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

Nature Genetics volume 48, pages 14811489 (2016) | Download Citation

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.

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Acknowledgements

We thank L. Yang (University of Washington, Seattle) for the gpIX reporter construct and the Genome Sequencing Facility, the Hartwell Center for Bioinformatics and Biotechnology, the Flow Cytometry and Cell Sorting core facility and the Biorepository of St. Jude Children's Research Hospital.

This work was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital, by a Stand Up to Cancer Innovative Research Grant and a St. Baldrick's Foundation Scholar Award (to C.G.M.), by a St. Baldrick's Consortium Award (to S.P.H.), by a Leukemia and Lymphoma Society Specialized Center of Research grant (to S.P.H. and C.G.M.), by a Lady Tata Memorial Trust Award (to I.I.), by a Leukemia and Lymphoma Society Special Fellow Award and Alex's Lemonade Stand Foundation Young Investigator Awards (to K.G.R.), by American Society of Hematology Scholar Awards (to C.G.M., P.N. and K.G.R.), by Dutch Cancer Society Fellowship KUN2012-5366 (to E. Waanders), by a St. Luke's Life Science Institute grant (to H.Y.), by National Cancer Institute grants P30 CA021765 (St. Jude Cancer Center Support Grant), U10 CA180820 (ECOG-ACRIN Operations), and CA180827 and CA196172 (to E.P.); U10 CA180861 (to C.D.B. and G.M.); U24 CA196171 (The Alliance NCTN Biorepository and Biospecimen Resource); CA145707 (to C.L.W. and C.G.M.); U01 CA157937 (to C.L.W. and S.P.H.), R00 CA188293 (to P.N.); and grants to the Children's Oncology Group: U10 CA98543 (Chair's grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center) and U24 CA114766 (Specimen Banking); and by National Institute of General Medical Sciences grant P50 GM115279 (to J.Z., J.Y., W.E.E., M.V.R., M.L.L. and C.G.M.). This project has been funded in whole or in part by federal funds from the National Cancer Institute, US National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

Author information

Author notes

    • Panagiotis Ntziachristos

    Present address: Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Affiliations

  1. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Jinghui Zhang
    • , Beisi Xu
    • , Gang Wu
    • , Yongjin Li
    • , Lei Wei
    • , Yu Liu
    • , Chunxu Qu
    • , Ji Wen
    • , Michael Edmonson
    • , John Easton
    • , Heather L Mulder
    • , Xiang Chen
    • , Scott Newman
    • , Xiaotu Ma
    • , Michael Rusch
    • , Pankaj Gupta
    • , Kristy Boggs
    •  & Bhavin Vadodaria
  2. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Kelly McCastlain
    • , Hiroki Yoshihara
    • , Yunchao Chang
    • , Michelle L Churchman
    • , Lei Wei
    • , Ilaria Iacobucci
    • , Debbie Payne-Turner
    • , Esmé Waanders
    • , Kathryn G Roberts
    • , Jing Ma
    • , Guangchun Song
    • , James Dalton
    • , Yanling Liu
    • , Sheila A Shurtleff
    • , Susana C Raimondi
    • , James R Downing
    •  & Charles G Mullighan
  3. Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Kerstin B Kaufmann
    • , Shin-ichiro Takayanagi
    • , Erno Wienholds
    •  & John E Dick
  4. Oncology Research Laboratories, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan.

    • Shin-ichiro Takayanagi
  5. Department of Human Genetics, Radboud University Medical Center and Radboud Center for Molecular Life Sciences, Nijmegen, the Netherlands.

    • Esmé Waanders
  6. Department of Pathology, New York University School of Medicine, New York, New York, USA.

    • Panagiotis Ntziachristos
    • , Sofia Bakogianni
    • , Jingjing Wang
    •  & Iannis Aifantis
  7. Howard Hughes Medical Institute, New York, New York, USA.

    • Iannis Aifantis
  8. Cytogenetics Core Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Marcus L Valentine
  9. McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.

    • Li Ding
    • , Charles Lu
    • , Robert S Fulton
    • , Lucinda Fulton
    • , Yashodhan Tabib
    • , Kerri Ochoa
    • , Elaine R Mardis
    •  & Richard K Wilson
  10. Department of Biostatistics, Colleges of Medicine, Public Health and Health Profession, University of Florida, Gainesville, Florida, USA.

    • Meenakshi Devidas
  11. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Deqing Pei
    •  & Cheng Cheng
  12. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Jun Yang
    • , William E Evans
    •  & Mary V Relling
  13. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Ching-Hon Pui
    •  & Sima Jeha
  14. Department of Pathology, Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, USA.

    • Richard C Harvey
    • , I-Ming L Chen
    •  & Cheryl L Willman
  15. Department of Hematology and Hematopoietic Cell Transplantation, Gehr Leukemia Center, City of Hope, Duarte, California, USA.

    • Guido Marcucci
  16. Division of Hematology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

    • Clara D Bloomfield
    • , Jessica Kohlschmidt
    •  & Krzysztof Mrózek
  17. Cancer Center, Montefiore Medical Center North Division, Bronx, New York, USA.

    • Elisabeth Paietta
  18. Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Martin S Tallman
  19. Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois, USA.

    • Wendy Stock
  20. Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Matthew C Foster
  21. Department of Medicine (Oncology), Albert Einstein College of Medicine, Montefiore Medical Center, New York, New York, USA.

    • Janis Racevskis
  22. Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.

    • Jacob M Rowe
  23. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Selina Luger
  24. Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Steven M Kornblau
  25. Department of Pediatrics, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

    • Stephen P Hunger
  26. Department of Pediatrics, Benioff Children's Hospital, University of California at San Francisco, San Francisco, California, USA.

    • Mignon L Loh

Consortia

  1. the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

    A list of members appears in the Supplementary Note.

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Contributions

J.Z., B.X., G.W., Yu Liu, L.W., Y. Li, C.Q., J. Wen, M.E., J.M., G.S., X.C., S.N., X.M., M.R., P.G., L.D., C.L., K.G.R., Y.T., R.C.H. and C.G.M. analyzed genomic data. K. McCastlain, I.I., H.Y., Y.C., D.P.-T., M.L.C., K.B.K., S.T., E. Waanders, E. Wienholds, P.N., S.B., J. Wang, I.A., K.G.R., J.E., H.L.M., K.B., B.V., J.D., Yanling Liu, M.L.V., R.C.H. and I.-M.L.C. performed experiments. R.S.F., L.F., K.O., E.R.M., R.K.W. and J.R.D. performed genome sequencing. M.D., D.P. and C.C. performed biostatistical analysis. J.Y., W.E.E., M.V.R., C.-H.P., S.J., C.L.W., G.M., C.D.B., J.K., K. Mrózek, E.P., M.S.T., W.S., M.C.F., J.R., J.M.R., S.L., S.M.K., S.A.S., S.C.R., S.P.H., M.L.L. and J.R.D. provided patient samples and data. J.E.D. provided reagents. J.Z., J.E.D. and C.G.M. designed experiments. J.Z. and C.G.M. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jinghui Zhang or Charles G Mullighan.

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https://doi.org/10.1038/ng.3691

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