Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells.
Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells.
复制标题
DOI：
10.1101/gad.280495.116
复制
发表时间：
2016-06-01
影响因子：
10.5
通讯作者：
Helin K
中科院分区：
文献类型：
--
作者：
Agger K;Miyagi S;Pedersen MT;Kooistra SM;Johansen JV;Helin K
Agger等人表明Jmjd 2/Kdm 4活性是MLL-AF 9易位的AML所需的。白细胞介素3受体α（Il 3ra）亚基的表达依赖于Jmjd 2/Kdm 4，其机制涉及从Il 3ra基因启动子中去除H3 K9 me 3。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。在这里，我们探索了使用H3 K9和H3 K36特异性脱甲基酶Jmjd 2/Kdm 4作为MLL-AF 9易位白血病中的推定药物靶标的可行性。使用Jmjd 2a，Jmjd 2b和Jmjd 2c条件性三重敲除小鼠，我们表明Jmjd 2/Kdm 4活性是MLL-AF 9易位AML在体内和体外所需的。我们证明了白细胞介素3受体α（IL 3ra也称为Cd 123）亚基的表达依赖于Jmjd 2/Kdm 4，其机制涉及从IL 3ra基因的启动子中去除H3 K9 me 3。重要的是，Il 3ra在Jmjd 2/Kdm 4敲除细胞中的异位表达证实了AML细胞存活对Jmjd 2/Kdm 4的需求，表明Il 3ra是白血病中Jmjd 2/Kdm 4的关键下游靶标。这些结果表明，JMJD 2/KDM 4蛋白是治疗AML的有希望的药物靶标。
Agger et al. show that Jmjd2/Kdm4 activities are required for MLL-AF9 translocated AML. Expression of the interleukin 3 receptor α (Il3ra) subunit is dependent on Jmjd2/Kdm4 through a mechanism involving removal of H3K9me3 from the promoter of the Il3ra gene. 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.