Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia

Panagiotis Ntziachristos, Aristotelis Tsirigos, G. Grant Welstead, Thomas Trimarchi, Sofia Bakogianni, Luyao Xu, Evangelia Loizou, Linda Holmfeldt, Alexandros Strikoudis, Bryan King, Jasper Mullenders, Jared Becksfort, Jelena Nedjic, Elisabeth M. Paietta, Martin S. Tallman, Jacob M. Rowe, Giovanni Tonon, Takashi Satoh, Laurens Kruidenier, Rab PrinjhaShizuo Akira, Pieter Van Vlierberghe, Adolfo A. Ferrando, Rudolf Jaenisch, Charles G. Mullighan, Iannis Aifantis

Research output: Contribution to journalArticle

184 Citations (Scopus)

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 identified<inf>2,3</inf>; however, 'epigenetic' drugs arenot currently used forT-ALLtreatment.Recently,wedescribedthat the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL<inf>4</inf>. 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 thatUTXfunctions as a tumour suppressor and is frequently genetically inactivated in T-ALL.Moreover, wedemonstrated that the smallmolecule 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.

Original languageEnglish (US)
Pages (from-to)513-517
Number of pages5
JournalNature
Volume514
Issue number7523
DOIs
StatePublished - Oct 23 2014

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Histones
Lysine
Epigenomics
Hematologic Neoplasms
Polycomb Repressive Complex 2
Pharmaceutical Preparations
Methylation
Chromatin
Neoplasms
Leukemia
Maintenance
Recurrence
Mutation
Growth
Genes
Proteins

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Ntziachristos, P., Tsirigos, A., Welstead, G. G., Trimarchi, T., Bakogianni, S., Xu, L., ... Aifantis, I. (2014). Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature, 514(7523), 513-517. https://doi.org/10.1038/nature13605

Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. / Ntziachristos, Panagiotis; Tsirigos, Aristotelis; Welstead, G. Grant; Trimarchi, Thomas; Bakogianni, Sofia; Xu, Luyao; Loizou, Evangelia; Holmfeldt, Linda; Strikoudis, Alexandros; King, Bryan; Mullenders, Jasper; Becksfort, Jared; Nedjic, Jelena; Paietta, Elisabeth M.; Tallman, Martin S.; Rowe, Jacob M.; Tonon, Giovanni; Satoh, Takashi; Kruidenier, Laurens; Prinjha, Rab; Akira, Shizuo; Van Vlierberghe, Pieter; Ferrando, Adolfo A.; Jaenisch, Rudolf; Mullighan, Charles G.; Aifantis, Iannis.

In: Nature, Vol. 514, No. 7523, 23.10.2014, p. 513-517.

Research output: Contribution to journalArticle

Ntziachristos, P, Tsirigos, A, Welstead, GG, Trimarchi, T, Bakogianni, S, Xu, L, Loizou, E, Holmfeldt, L, Strikoudis, A, King, B, Mullenders, J, Becksfort, J, Nedjic, J, Paietta, EM, Tallman, MS, Rowe, JM, Tonon, G, Satoh, T, Kruidenier, L, Prinjha, R, Akira, S, Van Vlierberghe, P, Ferrando, AA, Jaenisch, R, Mullighan, CG & Aifantis, I 2014, 'Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia', Nature, vol. 514, no. 7523, pp. 513-517. https://doi.org/10.1038/nature13605
Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature. 2014 Oct 23;514(7523):513-517. https://doi.org/10.1038/nature13605
Ntziachristos, Panagiotis ; Tsirigos, Aristotelis ; Welstead, G. Grant ; Trimarchi, Thomas ; Bakogianni, Sofia ; Xu, Luyao ; Loizou, Evangelia ; Holmfeldt, Linda ; Strikoudis, Alexandros ; King, Bryan ; Mullenders, Jasper ; Becksfort, Jared ; Nedjic, Jelena ; Paietta, Elisabeth M. ; Tallman, Martin S. ; Rowe, Jacob M. ; Tonon, Giovanni ; Satoh, Takashi ; Kruidenier, Laurens ; Prinjha, Rab ; Akira, Shizuo ; Van Vlierberghe, Pieter ; Ferrando, Adolfo A. ; Jaenisch, Rudolf ; Mullighan, Charles G. ; Aifantis, Iannis. / Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. In: Nature. 2014 ; Vol. 514, No. 7523. pp. 513-517.
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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 arenot currently used forT-ALLtreatment.Recently,wedescribedthat 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 thatUTXfunctions as a tumour suppressor and is frequently genetically inactivated in T-ALL.Moreover, wedemonstrated that the smallmolecule 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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AU - Ntziachristos, Panagiotis

AU - Tsirigos, Aristotelis

AU - Welstead, G. Grant

AU - Trimarchi, Thomas

AU - Bakogianni, Sofia

AU - Xu, Luyao

AU - Loizou, Evangelia

AU - Holmfeldt, Linda

AU - Strikoudis, Alexandros

AU - King, Bryan

AU - Mullenders, Jasper

AU - Becksfort, Jared

AU - Nedjic, Jelena

AU - Paietta, Elisabeth M.

AU - Tallman, Martin S.

AU - Rowe, Jacob M.

AU - Tonon, Giovanni

AU - Satoh, Takashi

AU - Kruidenier, Laurens

AU - Prinjha, Rab

AU - Akira, Shizuo

AU - Van Vlierberghe, Pieter

AU - Ferrando, Adolfo A.

AU - Jaenisch, Rudolf

AU - Mullighan, Charles G.

AU - Aifantis, Iannis

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N2 - 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 arenot currently used forT-ALLtreatment.Recently,wedescribedthat 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 thatUTXfunctions as a tumour suppressor and is frequently genetically inactivated in T-ALL.Moreover, wedemonstrated that the smallmolecule 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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