Modulators of histone demethylase JMJD1C selectively target leukemic stem cells,FEBS Open Bio

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Modulators of histone demethylase JMJD1C selectively target leukemic stem cells
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-12-01 , DOI: 10.1002/2211-5463.13054
Yong Yang ₁ , Xinjing Zhang ₂ , Xiaoyan Zhang ₃ , Yishu Wang ₁ , Xintong Wang ₄ , Linda Hu ₅ , Yao Zhao ₁ , Haihua Wang ₁ , Zhanju Wang ₆ , Haiying Wang ₆ , Lin Wang ₇ , Wilhelm G Dirks ₈ , Hans G Drexler ₈ , Xin Xu _{1,

9} , Zhenbo Hu ₁

Affiliation

Leukemic stem cells (LSCs) comprise a very rare cell population that results in the development of acute myeloid leukemia. The selective targeting of drivers in LSCs with small molecule inhibitors holds promise for treatment of acute myeloid leukemia. Recently, we reported the identification of inhibitors of the histone lysine demethylase JMJD1C that preferentially kill MLL rearranged acute leukemia cells. Here, we report the identification of jumonji domain modulator #7 (JDM‐7). Surface plasmon resonance analysis showed that JDM‐7 binds to JMJD1C and its family homolog JMJD1B. JDM‐7 did not significantly suppress cell proliferation in liquid cell culture at higher doses, although it led to a significant decrease in semi‐solid colony formation experiments at lower concentrations. Moreover, low doses of JDM‐7 did not suppress the proliferation of erythroid progenitor cells. We identified that JDM‐7 downregulates the LSC self‐renewal gene HOXA9 in leukemia cells. We further found that the structure of JDM‐7 is similar to that of tadalafil, a drug approved by the US Food and Drug Administration. Molecular docking and surface plasmon resonance analysis showed that tadalafil binds to JMJD1C. Moreover, similar to JDM‐7, tadalafil suppressed colony formation of leukemia cells in semi‐solid cell culture at a concentration that did not affect primary umbilical cord blood cells. In summary, we have identified JDM‐7 and tadalafil as potential JMJD1C modulators that selectively inhibit the growth of LSCs.

中文翻译：

组蛋白去甲基化酶 JMJD1C 调节剂选择性靶向白血病干细胞

白血病干细胞 (LSC) 是一种非常罕见的细胞群，可导致急性髓性白血病的发展。用小分子抑制剂选择性靶向 LSCs 中的驱动因子有望治疗急性髓性白血病。最近，我们报道了优先杀死MLL的组蛋白赖氨酸去甲基化酶 JMJD1C 抑制剂的鉴定。重排的急性白血病细胞。在这里，我们报告了 jumonji domain modulator #7 (JDM-7) 的识别。表面等离子共振分析表明，JDM-7 与 JMJD1C 及其家族同源物 JMJD1B 结合。JDM-7 在较高剂量下并没有显着抑制液体细胞培养物中的细胞增殖，尽管它在较低浓度下导致半固体集落形成实验显着减少。此外，低剂量的 JDM-7 并没有抑制红系祖细胞的增殖。我们发现 JDM-7 下调 LSC 自我更新基因HOXA9在白血病细胞中。我们进一步发现 JDM-7 的结构与美国食品和药物管理局批准的药物他达拉非的结构相似。分子对接和表面等离子共振分析表明，他达拉非与 JMJD1C 结合。此外，与 JDM-7 相似，他达拉非在不影响原代脐带血细胞的浓度下抑制半固体细胞培养中白血病细胞的集落形成。总之，我们已将 JDM-7 和他达拉非鉴定为潜在的 JMJD1C 调节剂，可选择性地抑制 LSC 的生长。

更新日期：2021-01-04

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