Research: XU and COLLEAGUES,

Listed in Issue 277

Abstract

XU and COLLEAGUES, 1 Laboratory for Stem Cell and Regenerative Medicine, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China; 2 College of Bioscience and Technology, Weifang, Shandong, China; 3 The School of Physics and Optoelectronic Engineering, Weifang University, Weifang, Shandong, China; 4 Upstate Medical University, Syracuse, NY; 5 Department of Human and Animal Cell Culture, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany; 6 The Department of Hematology, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China; 7 College of Pharmacy, Weifang Medical University, Weifang, Shandong, China studied small molecular modulators of JMJD1C [(Jumonji Domain Containing 1C) is a Protein Coding gene] as potential inhibitors of leukemia MLLr AL cells.

Background

Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL).

Methodology

The authors focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C [(Jumonji Domain Containing 1C) is a Protein Coding gene] to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening.

Results

JMJD1C Jumonji domain inhibitor 4 (JDI-4) and JDI-12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI-4 and JDI-12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI-4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI-4 and JDI-12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI-4 and JDI-12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI-16, among multiple compounds structurally akin to JDI-4/JDI-12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI-4/JDI-12. Mechanistically, JDI-16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI-16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI-16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI-16 collaborates with all-trans retinoic acid to repress MLLr AML cells.

Conclusion

In summary, the authors identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells.

References

Xin Xu  1   2 , Lin Wang  3 , Linda Hu  4 , Wilhelm G Dirks  5 , Yao Zhao  1 , Zhishuai Wei  2 , Dexiang Chen  2 , Zhaoliang Li  1 , Zhanju Wang  6 , Yangyang Han  2 , Liuya Wei  7 , Hans G Drexler  5 , Zhenbo Hu  1. Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells. Int J Cancer.  146(2):400-412. Jan 15 2020. doi: 10.1002/ijc.32552. Epub Jul 25 2019.

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