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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 is highly expressed in T-ALL and controls expression of important oncogenic targetsa, Size comparison of the spleens (left) and hematoxylin and eosin staining of the liver (right) of healthy (WT, top) and leukemic (T-ALL, bottom) mice. Arrows denote leukemic infiltration in the liver of T-ALL mouse. b, c, Protein (b) and transcript (c) levels of Jmjd3 and Utx demethylases in control T cells (CD4+/CD8+ thymocytes) and T-ALL. Representative sample (a, b) or the average (c) of three mice is shown. d, ChIP for Jmjd3 on Hes1 promoter in control T cells and T-ALL (left panel) and upon γSI treatment in T-ALL (right panel) (n=3). e, Expression analysis of JMJD3 and HES1 amongst 595 primary samples of T (83 samples)- and B (23)-cell Leukemia, Myeloid leukemia (537) as well as physiological T cell subsets (24)23. P–values (Wilcoxon test), JMJD3: T-ALL vs T cells: 4.0×10−6, T-ALL vs AML: 1.1×10−13, T-ALL vs B-ALL: 2.2×10−5. Hes1: T-ALL vs T cells: 3.7×10−4, T-ALL vs AML: 3.5×10−43, T-ALL vs B-ALL: 1.3×10−6. f, Snapshots of JMJD3 binding in human T-ALL. Three NOTCH1 targets and the Interferon beta (IFNβ) gene (negative control) are shown.
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Figure 1: JMJD3 is highly expressed in T-ALL and controls expression of important oncogenic targetsa, Size comparison of the spleens (left) and hematoxylin and eosin staining of the liver (right) of healthy (WT, top) and leukemic (T-ALL, bottom) mice. Arrows denote leukemic infiltration in the liver of T-ALL mouse. b, c, Protein (b) and transcript (c) levels of Jmjd3 and Utx demethylases in control T cells (CD4+/CD8+ thymocytes) and T-ALL. Representative sample (a, b) or the average (c) of three mice is shown. d, ChIP for Jmjd3 on Hes1 promoter in control T cells and T-ALL (left panel) and upon γSI treatment in T-ALL (right panel) (n=3). e, Expression analysis of JMJD3 and HES1 amongst 595 primary samples of T (83 samples)- and B (23)-cell Leukemia, Myeloid leukemia (537) as well as physiological T cell subsets (24)23. P–values (Wilcoxon test), JMJD3: T-ALL vs T cells: 4.0×10−6, T-ALL vs AML: 1.1×10−13, T-ALL vs B-ALL: 2.2×10−5. Hes1: T-ALL vs T cells: 3.7×10−4, T-ALL vs AML: 3.5×10−43, T-ALL vs B-ALL: 1.3×10−6. f, Snapshots of JMJD3 binding in human T-ALL. Three NOTCH1 targets and the Interferon beta (IFNβ) gene (negative control) are shown.

Mentions: We have generated and studied NOTCH1-induced T-ALL animal models4 (Fig. 1a), as activating mutations of NOTCH1 are a defining feature of this disease21. Jmjd3 mRNA and protein expression levels were significantly higher in leukemic cells when compared to untransformed CD4+/CD8+ control T cells that exhibit low levels of active Notch1 whereas Utx (and Ezh24) expression did not change significantly (Fig. 1b, c and Supplementary File 2/Table 1) upon transformation. It was previously shown that NFkB controls JMJD3 expression during inflammation11 and that NOTCH1 induces the NFkB pathway in T-ALL22. Here, we were able to show increased expression of the p65 (Rela) subunit of NFkB and its binding-but not Notch1- on Jmjd3 control elements in T-ALL cells (Extended Data Fig. 1a, b). Modulation of the levels of intracellular NOTCH1 or activity of NFkB pathway decreased significantly the amounts of NFkB bound on the Jmjd3 elements, as well as Jmjd3 mRNA expression (Extended Data Fig. 1b–f). We then probed for Jmjd3 binding on specific oncogenic loci, previously shown to be important in T-ALL4. We found that Jmjd3 binding was highly enriched on the Hes1 promoter (Fig. 1d, left), depended on the activation of the Notch1 pathway and negatively correlated with H3K27m3 levels (Extended Data Fig. 1g, h).


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 is highly expressed in T-ALL and controls expression of important oncogenic targetsa, Size comparison of the spleens (left) and hematoxylin and eosin staining of the liver (right) of healthy (WT, top) and leukemic (T-ALL, bottom) mice. Arrows denote leukemic infiltration in the liver of T-ALL mouse. b, c, Protein (b) and transcript (c) levels of Jmjd3 and Utx demethylases in control T cells (CD4+/CD8+ thymocytes) and T-ALL. Representative sample (a, b) or the average (c) of three mice is shown. d, ChIP for Jmjd3 on Hes1 promoter in control T cells and T-ALL (left panel) and upon γSI treatment in T-ALL (right panel) (n=3). e, Expression analysis of JMJD3 and HES1 amongst 595 primary samples of T (83 samples)- and B (23)-cell Leukemia, Myeloid leukemia (537) as well as physiological T cell subsets (24)23. P–values (Wilcoxon test), JMJD3: T-ALL vs T cells: 4.0×10−6, T-ALL vs AML: 1.1×10−13, T-ALL vs B-ALL: 2.2×10−5. Hes1: T-ALL vs T cells: 3.7×10−4, T-ALL vs AML: 3.5×10−43, T-ALL vs B-ALL: 1.3×10−6. f, Snapshots of JMJD3 binding in human T-ALL. Three NOTCH1 targets and the Interferon beta (IFNβ) gene (negative control) are shown.
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Figure 1: JMJD3 is highly expressed in T-ALL and controls expression of important oncogenic targetsa, Size comparison of the spleens (left) and hematoxylin and eosin staining of the liver (right) of healthy (WT, top) and leukemic (T-ALL, bottom) mice. Arrows denote leukemic infiltration in the liver of T-ALL mouse. b, c, Protein (b) and transcript (c) levels of Jmjd3 and Utx demethylases in control T cells (CD4+/CD8+ thymocytes) and T-ALL. Representative sample (a, b) or the average (c) of three mice is shown. d, ChIP for Jmjd3 on Hes1 promoter in control T cells and T-ALL (left panel) and upon γSI treatment in T-ALL (right panel) (n=3). e, Expression analysis of JMJD3 and HES1 amongst 595 primary samples of T (83 samples)- and B (23)-cell Leukemia, Myeloid leukemia (537) as well as physiological T cell subsets (24)23. P–values (Wilcoxon test), JMJD3: T-ALL vs T cells: 4.0×10−6, T-ALL vs AML: 1.1×10−13, T-ALL vs B-ALL: 2.2×10−5. Hes1: T-ALL vs T cells: 3.7×10−4, T-ALL vs AML: 3.5×10−43, T-ALL vs B-ALL: 1.3×10−6. f, Snapshots of JMJD3 binding in human T-ALL. Three NOTCH1 targets and the Interferon beta (IFNβ) gene (negative control) are shown.
Mentions: We have generated and studied NOTCH1-induced T-ALL animal models4 (Fig. 1a), as activating mutations of NOTCH1 are a defining feature of this disease21. Jmjd3 mRNA and protein expression levels were significantly higher in leukemic cells when compared to untransformed CD4+/CD8+ control T cells that exhibit low levels of active Notch1 whereas Utx (and Ezh24) expression did not change significantly (Fig. 1b, c and Supplementary File 2/Table 1) upon transformation. It was previously shown that NFkB controls JMJD3 expression during inflammation11 and that NOTCH1 induces the NFkB pathway in T-ALL22. Here, we were able to show increased expression of the p65 (Rela) subunit of NFkB and its binding-but not Notch1- on Jmjd3 control elements in T-ALL cells (Extended Data Fig. 1a, b). Modulation of the levels of intracellular NOTCH1 or activity of NFkB pathway decreased significantly the amounts of NFkB bound on the Jmjd3 elements, as well as Jmjd3 mRNA expression (Extended Data Fig. 1b–f). We then probed for Jmjd3 binding on specific oncogenic loci, previously shown to be important in T-ALL4. We found that Jmjd3 binding was highly enriched on the Hes1 promoter (Fig. 1d, left), depended on the activation of the Notch1 pathway and negatively correlated with H3K27m3 levels (Extended Data Fig. 1g, h).

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