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Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components <jats:italic>via<\/jats:italic> virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI\u20104) and JDI\u201012 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI\u20104 and JDI\u201012 bind to JMJD1C and its family homolog KDM3B with modest affinity. <jats:italic>In vitro<\/jats:italic> demethylation assays showed that JDI\u20104 can reverse the H3K9 demethylation conferred by KDM3B. <jats:italic>In vivo<\/jats:italic> demethylation assays indicated that JDI\u20104 and JDI\u201012 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI\u20104 and JDI\u201012 kill <jats:italic>MLL<\/jats:italic>r AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI\u201016, among multiple compounds structurally akin to JDI\u20104\/JDI\u201012, exhibits superior killing activities against malignant hematopoietic cells compared to JDI\u20104\/JDI\u201012. Mechanistically, JDI\u201016 not only induces apoptosis but also differentiation of <jats:italic>MLL<\/jats:italic>r AL cells. RNA sequencing and quantitative PCR showed that JDI\u201016 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI\u201016 downregulates lactic acids, NADP<jats:sup>+<\/jats:sup> and other metabolites. Moreover, JDI\u201016 collaborates with all\u2010trans retinoic acid to repress <jats:italic>MLL<\/jats:italic>r AML cells. In summary, we identified <jats:italic>bona fide<\/jats:italic> JMJD1C inhibitors that induce preferential death of <jats:italic>MLL<\/jats:italic>r AL cells.<\/jats:p>","DOI":"10.1002\/ijc.32552","type":"journal-article","created":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T17:46:08Z","timestamp":1562262368000},"page":"400-412","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells"],"prefix":"10.1002","volume":"146","author":[{"given":"Xin","family":"Xu","sequence":"first","affiliation":[{"name":"Laboratory for Stem Cell and Regenerative Medicine The Affiliated Hospital of Weifang Medical University  Weifang Shandong China"},{"name":"College of Bioscience and Technology  Weifang Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"The 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