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Abstract

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders1, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified2,3; however, ‘epigenetic’ drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL4. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.

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Change history

  • 23 October 2014

    A minor change was made to the author list.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

The high-throughput sequencing data have been deposited in the Gene Expression Omnibus with accession number GSE56696.

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Acknowledgements

We thank the members of the Aifantis laboratory and J. Siegle for discussions throughout the duration of the project; S. Shen for discussions on the analysis of sequencing data; GlaxoSmithKline for the GSKJ4 and GSKJ5 inhibitory compounds; A. Heguy and the NYU Genome Technology Center (supported in part by National Institutes of Health (NIH)/National Cancer Institute (NCI) grant P30 CA016087-30) for assistance with sequencing experiments; the NYU Flow Cytometry facility (supported in part by NIH/NCI grant 5P30CA16087-31) for cell sorting; the NYU Histology Core (5P30CA16087-31) and the NYU mouse facility (NYU Cancer Institute Center Grant 5P30CA16087-31); G. Natoli for providing the anti-JMJD3 antibody; J. Zhang for help with the analysis of the mutation data; and I. Rigo for technical support. I.A. was supported by the NIH (grants 1RO1CA133379, 1RO1CA105129, 1RO1CA149655, 5RO1CA173636 and 5RO1CA169784). J.N. was supported by the Damon Runyon Cancer Research Foundation. B.K. was supported by the NYU Cell and Molecular Biology Training Program. P.N. was supported by fellowships from Lady Tata Memorial Trust for leukaemia and the American Society of Hematology and NIH/NCI (K99CA188293). T.T. is supported by the NIH training grant 5 T32 CA009161-37. P.V.V. was supported by the Research Foundation Flanders and an Odysseus type II grant. Moreover, this study was supported by an NIH grant (R37-HD04502) to R.J., the ECOG tumour bank, an NIH grant (R01CA120196) to A.A.F.; NCI grants (U24 CA114737 and U10 CA21115) to E.P. and the Stand Up To Cancer Innovative Research Award (A.A.F.). I.A. was also supported by the William Lawrence and Blanche Hughes Foundation, The Leukemia & Lymphoma Society, the Ralph S. French Charitable Foundation Trust, The Chemotherapy Foundation, The V Foundation for Cancer Research and the St. Baldrick’s Foundation. I.A. is a Howard Hughes Medical Institute Early Career Scientist. A.T. carried out part of this work while at the Computational Biology Center, IBM Research, Yorktown Heights, New York.

Author information

Author notes

    • Panagiotis Ntziachristos
    •  & Aristotelis Tsirigos

    These authors contributed equally to this work.

    • G. Grant Welstead

    Present address: Editas Medicine, Cambridge, Massachusetts 02142, USA.

Affiliations

  1. Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA

    • Panagiotis Ntziachristos
    • , Aristotelis Tsirigos
    • , Thomas Trimarchi
    • , Sofia Bakogianni
    • , Evangelia Loizou
    • , Alexandros Strikoudis
    • , Bryan King
    • , Jasper Mullenders
    • , Jelena Nedjic
    •  & Iannis Aifantis
  2. NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA

    • Panagiotis Ntziachristos
    • , Thomas Trimarchi
    • , Sofia Bakogianni
    • , Evangelia Loizou
    • , Alexandros Strikoudis
    • , Bryan King
    • , Jasper Mullenders
    • , Jelena Nedjic
    •  & Iannis Aifantis
  3. Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, New York 10016, USA

    • Aristotelis Tsirigos
  4. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA

    • G. Grant Welstead
    •  & Rudolf Jaenisch
  5. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • G. Grant Welstead
    •  & Rudolf Jaenisch
  6. Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA

    • Luyao Xu
    • , Pieter Van Vlierberghe
    •  & Adolfo A. Ferrando
  7. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Linda Holmfeldt
    •  & Charles G. Mullighan
  8. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Jared Becksfort
  9. Montefiore Medical Center North, Bronx, New York, New York 10467, USA

    • Elisabeth Paietta
  10. Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Martin S. Tallman
  11. Technion, Israel Institute of Technology, Haifa 31096, Israel

    • Jacob M. Rowe
  12. Shaare Zedek Medical Center, Jerusalem 9103102, Israel

    • Jacob M. Rowe
  13. Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132 Milan, Italy

    • Giovanni Tonon
  14. Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan

    • Takashi Satoh
    •  & Shizuo Akira
  15. Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1Yamada-oka, Suita, Osaka 565-0871, Japan

    • Takashi Satoh
    •  & Shizuo Akira
  16. Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, GunnelsWood Road, Stevenage SG1 2NY, UK

    • Laurens Kruidenier
    •  & Rab Prinjha
  17. Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium

    • Pieter Van Vlierberghe
  18. Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA

    • Adolfo A. Ferrando
  19. Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA

    • Adolfo A. Ferrando

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Contributions

I.A. and P.N. designed the experiments and wrote the manuscript. P.N. performed most of the experiments. A.T. designed and performed the analysis of genome-wide data and wrote the manuscript. T.T., E.L., A.S., J.M., B.K., S.B. and J.N. performed experiments and contributed ideas. G.T. provided materials and tips related to the study. A.A.F. and L.X. designed and performed xenograft luciferase experiments and helped with ideas and concepts. P.V.V., E.P., M.S.T., J.M.R. and A.A.F. performed and analysed the mutational studies in adult T-ALL. G.G.W., R.J., T.S. and S.A. provided mouse tissues and helped with ideas and concepts. L.K. and R.P. helped with guidance on the biology and use of GSKJ inhibitors and with manuscript preparation. L.H., J.B. and C.G.M. performed and analysed the mutational studies in paediatric T-ALL.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Aristotelis Tsirigos or Charles G. Mullighan or Iannis Aifantis.

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DOI

https://doi.org/10.1038/nature13605

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