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

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 2,3; however, 'epigenetic' drugs arenot currently used forT-ALLtreatment.Recently,wedescribedthat the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL 4. 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.