Limits...
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: 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.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

Physiological development of the hematopoietic system in the absence of Jmjd3a, b, Targeting scheme for the generation of Jmjd3−/− allele (a) and PCR-based quantification of the wild-type and mutant transcripts (b) using a specific primer set for the 3’ end of Jmjd3 cDNA. c, d, Analysis of the fetal liver for lineage markers (c) as well as bone marrow (d) of recipients for hematopoietic progenitors (lineage−, c-kit+, sca+ (LSK) population) for the Jmjd3+/+ and Jmjd3−/− genotypes. Representative plots of three independent experiments are shown. e–g, Analysis of major thymic subsets in Jmjd3+/+ (n=7) and Jmjd3−/− (n=7). Schematic representation of FACS analysis performed (e). Relative proportions of major cell populations in the thymi of Jmjd3+/+ and Jmjd3−/− background (f). mRNA expression of Jmjd3 gene in different stages of thymic development (g). h, and expression of Notch1 target (like Hes1, n=7) in CD4+/CD8+ double positive and CD4− CD8−CD25+ lymphocyte progenitor cells. Representative plots (e) as well as average representation (g, h) of seven independent thymi are shown.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4209203&req=5

Figure 10: Physiological development of the hematopoietic system in the absence of Jmjd3a, b, Targeting scheme for the generation of Jmjd3−/− allele (a) and PCR-based quantification of the wild-type and mutant transcripts (b) using a specific primer set for the 3’ end of Jmjd3 cDNA. c, d, Analysis of the fetal liver for lineage markers (c) as well as bone marrow (d) of recipients for hematopoietic progenitors (lineage−, c-kit+, sca+ (LSK) population) for the Jmjd3+/+ and Jmjd3−/− genotypes. Representative plots of three independent experiments are shown. e–g, Analysis of major thymic subsets in Jmjd3+/+ (n=7) and Jmjd3−/− (n=7). Schematic representation of FACS analysis performed (e). Relative proportions of major cell populations in the thymi of Jmjd3+/+ and Jmjd3−/− background (f). mRNA expression of Jmjd3 gene in different stages of thymic development (g). h, and expression of Notch1 target (like Hes1, n=7) in CD4+/CD8+ double positive and CD4− CD8−CD25+ lymphocyte progenitor cells. Representative plots (e) as well as average representation (g, h) of seven independent thymi are shown.

Mentions: Jmjd3−/− mice28, in turn, lack the catalytic domain of the Jmjd3 protein (Extended Data Fig. 6a, b) and die perinatally28. Hematopoiesis and T cell development were largely unaffected by the absence of Jmjd3 (Extended Data Fig. 6c–h). Genetic ablation of Jmjd3 in T-ALL led to fewer leukemic blasts in the peripheral blood, significantly reduced leukemic infiltration into spleen and liver and improved survival rates in recipients (Extended Data Fig. 7a–f), consistent with an oncogenic role of Jmjd3. These striking phenotypes supported our previous in vitro and in vivo findings and led us to further explore the therapeutic potential of targeting Jmjd3 activity in T-ALL.


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)

Physiological development of the hematopoietic system in the absence of Jmjd3a, b, Targeting scheme for the generation of Jmjd3−/− allele (a) and PCR-based quantification of the wild-type and mutant transcripts (b) using a specific primer set for the 3’ end of Jmjd3 cDNA. c, d, Analysis of the fetal liver for lineage markers (c) as well as bone marrow (d) of recipients for hematopoietic progenitors (lineage−, c-kit+, sca+ (LSK) population) for the Jmjd3+/+ and Jmjd3−/− genotypes. Representative plots of three independent experiments are shown. e–g, Analysis of major thymic subsets in Jmjd3+/+ (n=7) and Jmjd3−/− (n=7). Schematic representation of FACS analysis performed (e). Relative proportions of major cell populations in the thymi of Jmjd3+/+ and Jmjd3−/− background (f). mRNA expression of Jmjd3 gene in different stages of thymic development (g). h, and expression of Notch1 target (like Hes1, n=7) in CD4+/CD8+ double positive and CD4− CD8−CD25+ lymphocyte progenitor cells. Representative plots (e) as well as average representation (g, h) of seven independent thymi are shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209203&req=5

Figure 10: Physiological development of the hematopoietic system in the absence of Jmjd3a, b, Targeting scheme for the generation of Jmjd3−/− allele (a) and PCR-based quantification of the wild-type and mutant transcripts (b) using a specific primer set for the 3’ end of Jmjd3 cDNA. c, d, Analysis of the fetal liver for lineage markers (c) as well as bone marrow (d) of recipients for hematopoietic progenitors (lineage−, c-kit+, sca+ (LSK) population) for the Jmjd3+/+ and Jmjd3−/− genotypes. Representative plots of three independent experiments are shown. e–g, Analysis of major thymic subsets in Jmjd3+/+ (n=7) and Jmjd3−/− (n=7). Schematic representation of FACS analysis performed (e). Relative proportions of major cell populations in the thymi of Jmjd3+/+ and Jmjd3−/− background (f). mRNA expression of Jmjd3 gene in different stages of thymic development (g). h, and expression of Notch1 target (like Hes1, n=7) in CD4+/CD8+ double positive and CD4− CD8−CD25+ lymphocyte progenitor cells. Representative plots (e) as well as average representation (g, h) of seven independent thymi are shown.
Mentions: Jmjd3−/− mice28, in turn, lack the catalytic domain of the Jmjd3 protein (Extended Data Fig. 6a, b) and die perinatally28. Hematopoiesis and T cell development were largely unaffected by the absence of Jmjd3 (Extended Data Fig. 6c–h). Genetic ablation of Jmjd3 in T-ALL led to fewer leukemic blasts in the peripheral blood, significantly reduced leukemic infiltration into spleen and liver and improved survival rates in recipients (Extended Data Fig. 7a–f), consistent with an oncogenic role of Jmjd3. These striking phenotypes supported our previous in vitro and in vivo findings and led us to further explore the therapeutic potential of targeting Jmjd3 activity in T-ALL.

Bottom Line: 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.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