急性淋巴细胞白血病(T-ALL)是一种预后很差的血源性恶性肿瘤，因缺乏无毒、靶向性治疗措施，其复发率达25%。有多种针对不同造血失调的关键表观遗传因子的药物已获审批；在不同的白血病种类中，也确定了多个影响染色质调节因子的突变型；但是还没有针对表观遗传的药物被用于急性淋巴细胞白血病的治疗中。近来，我们描述了多梳抑制复合体2 (polycomb repressive complex 2，PRC2) 在T-ALL中发挥抑制作用。在此，我们将描述组蛋白H3赖氨酸27（histone 3 lysine 27，H3K27）脱甲基酶：JMJD3和UTX在T-ALL中的作用。我们的结果显示JMJD3为T-ALL发病和维持的必要因子，它通过调节H3K27甲基化控制了多个重要的致癌基因。与之形成对比，我们发现UTX作为肿瘤抑制因子在T-ALL中发挥作用，该分子经常处于基因失活状态。另外，我们证明小分子抑制因子GSKJ4通过靶向控制JMJD3的活性影响T-ALL生长。这些结果显示两种具有相似功能的酶在同一疾病中发挥了相反的作用，从而为使用表观遗传抑制因子治疗血液系统恶性肿瘤提供了新途径。

链接：http://www.nature.com/nature/journal/v514/n7523/full/nature13605.html

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

摘要：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 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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