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

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 E, 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 - Nature (2014)

Bottom Line: Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment.By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [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 [3].

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 disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; 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-ALL. 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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JMJD3 as a pivotal factor in NOTCH1-mediated oncogenic activation in T cell leukemiaa, Schematic representation of the H3K27me3 writer (polycomb complex, right panel) and eraser JMJD3 (left panel). EZH2 entails the catalytic subunit of the complex through its SET domain, whereas EED subunit recognizes the H3K27me3 mark and helps polycomb binding. JmjC domain activity is inhibited by the small molecule inhibitor GSKJ4. b, Main notion of the key role of JMJD3 in the NOTCH1 transcriptional complex’ Before activation of the NOTCH1 signaling pathway the promoters of classical NOTCH1 targets are bound by RBBJk together with components of the co-repressor complexes and poycomb repressive complex 2 (PRC2), leading to low gene expression. After binding of NOTCH1 and its co-activator MAML1 the genes are activated through recruitment of JMJD3 and MLL complex, with simultaneous eviction of PRC2, which leads to demethylation of H3K27me3 and methylation of H3K4me3.
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Figure 14: JMJD3 as a pivotal factor in NOTCH1-mediated oncogenic activation in T cell leukemiaa, Schematic representation of the H3K27me3 writer (polycomb complex, right panel) and eraser JMJD3 (left panel). EZH2 entails the catalytic subunit of the complex through its SET domain, whereas EED subunit recognizes the H3K27me3 mark and helps polycomb binding. JmjC domain activity is inhibited by the small molecule inhibitor GSKJ4. b, Main notion of the key role of JMJD3 in the NOTCH1 transcriptional complex’ Before activation of the NOTCH1 signaling pathway the promoters of classical NOTCH1 targets are bound by RBBJk together with components of the co-repressor complexes and poycomb repressive complex 2 (PRC2), leading to low gene expression. After binding of NOTCH1 and its co-activator MAML1 the genes are activated through recruitment of JMJD3 and MLL complex, with simultaneous eviction of PRC2, which leads to demethylation of H3K27me3 and methylation of H3K4me3.

Mentions: We propose here targeting of JMJD3 as a novel therapy option for pediatric and adult T-ALL. This proposal is based on recent studies2,4,29 that demonstrate that H3K27me3 catalyzed by PRC2 complex plays a key role in T-ALL, through antagonism with oncogenic NOTCH1. We demonstrate here that NOTCH1-mediated JMJD3 recruitment on promoters could explain this antagonism (Extended Data Fig. 10, see also Supplementary File 1 for extended discussion). We propose that NOTCH1 recruitment could lead to PRC2 eviction due to active demethylation of H3K27 through the catalytic activity of JMJD3 and the recruitment of JMJD3 to target promoters. On the other hand, the reported increased levels of the activating H3K4me3 mark on a large fraction of NOTCH1 targets30 (Fig. 4f) can be explained by the fact that NOTCH1 has the ability to participate in MLL complexes (Extended Data Fig. 2 and 10). Moreover we demonstrate antitumorigenic activities of the GSKJ4 inhibitor5 and specificity for T-ALL cells. Obviously, we cannot exclude the possibility that GSKJ4 could potentially affect other important epigenetic modulators or signaling pathways. Nevertheless, we believe that the main action of this inhibitor in T-ALL is channeled through the inhibition of JMJD3 activity and propose that such compounds should be tested either as single drugs or in combination to standard chemotherapy.


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

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 E, 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 - Nature (2014)

JMJD3 as a pivotal factor in NOTCH1-mediated oncogenic activation in T cell leukemiaa, Schematic representation of the H3K27me3 writer (polycomb complex, right panel) and eraser JMJD3 (left panel). EZH2 entails the catalytic subunit of the complex through its SET domain, whereas EED subunit recognizes the H3K27me3 mark and helps polycomb binding. JmjC domain activity is inhibited by the small molecule inhibitor GSKJ4. b, Main notion of the key role of JMJD3 in the NOTCH1 transcriptional complex’ Before activation of the NOTCH1 signaling pathway the promoters of classical NOTCH1 targets are bound by RBBJk together with components of the co-repressor complexes and poycomb repressive complex 2 (PRC2), leading to low gene expression. After binding of NOTCH1 and its co-activator MAML1 the genes are activated through recruitment of JMJD3 and MLL complex, with simultaneous eviction of PRC2, which leads to demethylation of H3K27me3 and methylation of H3K4me3.
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Related In: Results  -  Collection

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Figure 14: JMJD3 as a pivotal factor in NOTCH1-mediated oncogenic activation in T cell leukemiaa, Schematic representation of the H3K27me3 writer (polycomb complex, right panel) and eraser JMJD3 (left panel). EZH2 entails the catalytic subunit of the complex through its SET domain, whereas EED subunit recognizes the H3K27me3 mark and helps polycomb binding. JmjC domain activity is inhibited by the small molecule inhibitor GSKJ4. b, Main notion of the key role of JMJD3 in the NOTCH1 transcriptional complex’ Before activation of the NOTCH1 signaling pathway the promoters of classical NOTCH1 targets are bound by RBBJk together with components of the co-repressor complexes and poycomb repressive complex 2 (PRC2), leading to low gene expression. After binding of NOTCH1 and its co-activator MAML1 the genes are activated through recruitment of JMJD3 and MLL complex, with simultaneous eviction of PRC2, which leads to demethylation of H3K27me3 and methylation of H3K4me3.
Mentions: We propose here targeting of JMJD3 as a novel therapy option for pediatric and adult T-ALL. This proposal is based on recent studies2,4,29 that demonstrate that H3K27me3 catalyzed by PRC2 complex plays a key role in T-ALL, through antagonism with oncogenic NOTCH1. We demonstrate here that NOTCH1-mediated JMJD3 recruitment on promoters could explain this antagonism (Extended Data Fig. 10, see also Supplementary File 1 for extended discussion). We propose that NOTCH1 recruitment could lead to PRC2 eviction due to active demethylation of H3K27 through the catalytic activity of JMJD3 and the recruitment of JMJD3 to target promoters. On the other hand, the reported increased levels of the activating H3K4me3 mark on a large fraction of NOTCH1 targets30 (Fig. 4f) can be explained by the fact that NOTCH1 has the ability to participate in MLL complexes (Extended Data Fig. 2 and 10). Moreover we demonstrate antitumorigenic activities of the GSKJ4 inhibitor5 and specificity for T-ALL cells. Obviously, we cannot exclude the possibility that GSKJ4 could potentially affect other important epigenetic modulators or signaling pathways. Nevertheless, we believe that the main action of this inhibitor in T-ALL is channeled through the inhibition of JMJD3 activity and propose that such compounds should be tested either as single drugs or in combination to standard chemotherapy.

Bottom Line: Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment.By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [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 [3].

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 disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; 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-ALL. 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.

Show MeSH
Related in: MedlinePlus