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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Gene Expression Omnibus
The high-throughput sequencing data have been deposited in the Gene Expression Omnibus with accession number GSE56696.
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.
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Frontiers in Oncology (2019)