Jmjd2/Kdm4去甲基化酶是白细胞介素3受体α链（Il3ra）表达及急性髓性白血病细胞存活所必需的。
Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells.
作者信息
Agger Karl, Miyagi Satoru, Pedersen Marianne Terndrup, Kooistra Susanne M, Johansen Jens Vilstrup, Helin Kristian
机构信息
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark; Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark;
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark; Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark; The Danish Stem Cell Center (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
出版信息
Genes Dev. 2016 Jun 1;30(11):1278-88. doi: 10.1101/gad.280495.116. Epub 2016 Jun 2.
Acute myeloid leukemias (AMLs) with a rearrangement of the mixed-linage leukemia (MLL) gene are aggressive hematopoietic malignancies. Here, we explored the feasibility of using the H3K9- and H3K36-specific demethylases Jmjd2/Kdm4 as putative drug targets in MLL-AF9 translocated leukemia. Using Jmjd2a, Jmjd2b, and Jmjd2c conditional triple-knockout mice, we show that Jmjd2/Kdm4 activities are required for MLL-AF9 translocated AML in vivo and in vitro. We demonstrate that expression of the interleukin 3 receptor α (Il3ra also known as Cd123) subunit is dependent on Jmjd2/Kdm4 through a mechanism involving removal of H3K9me3 from the promoter of the Il3ra gene. Importantly, ectopic expression of Il3ra in Jmjd2/Kdm4 knockout cells alleviates the requirement of Jmjd2/Kdm4 for the survival of AML cells, showing that Il3ra is a critical downstream target of Jmjd2/Kdm4 in leukemia. These results suggest that the JMJD2/KDM4 proteins are promising drug targets for the treatment of AML.
伴有混合系白血病（MLL）基因重排的急性髓系白血病（AML）是侵袭性造血系统恶性肿瘤。在此，我们探讨了将H3K9和H3K36特异性去甲基化酶Jmjd2/Kdm4作为MLL-AF9易位白血病潜在药物靶点的可行性。利用Jmjd2a、Jmjd2b和Jmjd2c条件性三敲除小鼠，我们发现Jmjd2/Kdm4活性在体内和体外对于MLL-AF9易位AML都是必需的。我们证明白细胞介素3受体α（Il3ra，也称为Cd123）亚基的表达通过一种机制依赖于Jmjd2/Kdm4，该机制涉及从Il3ra基因启动子上去除H3K9me3。重要的是，Il3ra在Jmjd2/Kdm4敲除细胞中的异位表达减轻了Jmjd2/Kdm4对AML细胞存活的需求，表明Il3ra是白血病中Jmjd2/Kdm4的关键下游靶点。这些结果表明JMJD2/KDM4蛋白是治疗AML的有前景的药物靶点。
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