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  • JMJD C is another JmjC


    JMJD1C is another JmjC domain protein discovered as a putative oncogene in shRNA screens in MLL-AF9-, HOXA9-, and AML1-ETO-driven AML 40, 41, 42. Depletion of JMJD1C decreased the frequency of LICs by inducing their differentiation and impaired the growth and establishment of leukemia in serial transplantation experiments. Notably, although JMJD1C is important for the maintenance of the malignant phenotype, it is dispensable for leukemia initiation [41]. Although originally reported to be an H3K9me2/me1 demethylase leading to transcriptional activation, subsequent studies failed to detect demethylase activity for JMJD1C 40, 41, 42. Therefore, the question of whether the role of JMJD1C in leukemia maintenance relies on its demethylation activity remains open. Considering that the loss of JMJD1C caused minor defects in normal hematopoiesis, its inhibition with small-molecule inhibitors may be beneficial in the aforementioned types of AML with minimal adverse effects.
    Conclusions and future directions A hallmark of hematopoietic malignancies is a block in cellular differentiation, which causes accumulation of progenitor ML-7 hydrochloride and facilitates cell transformation in the context of additional genetic and epigenetic changes. Therefore, restoring differentiation may represent an “Achilles heel” for successful remission and treatment of leukemia by forcing LICs to differentiate to more mature cells that can be eradicated by current treatments. As reviewed here, strong evidence indicates that lysine-specific histone demethylases are major regulators of cell fate and lineage commitment decisions, and their deregulation facilitates hematopoietic transformation, primarily through maintaining leukemic cells in an undifferentiated and drug-resistant state (Fig. 1). Therefore, combining histone demethylase–specific, small molecule inhibitors with current treatments is a promising avenue to promote the differentiation and eradication of blast cells. Further studies using animal models are needed to delineate the complexity of those circuitries and to determine the appropriate therapeutic window to alleviate adverse effects in normal hematopoiesis.
    Acknowledgments This work was supported by an Alex's Lemonade Stand Foundation Young Investigator Award and National Cancer Institute GrantsR00CA158582 and R21CA182662, awarded to AT.
    Introduction Histone modifications, which include histone methylation, acetylation and ubiquitination, play key roles in epigenetic mechanisms (Justin G et al., 2002; Alvarez-Venegas R et al., 2007; Neilson et al., 2007). Currently reported histone demethylases include LSD1 (Lysine specific demethylase l) and JHDM (JmjC-domain-containing histone demethylases) (Lan F et al., 2009; Pikaard and Mittelsten Scheid, 2014; To and Kim, 2014). The JmjC protein family containing the Jumonji C (JMJC) domain, the functional center, has the function of histone demethylation and regulates metabolic activity (Chen Z et al., 2006; Robert et al., 2006; Mosammaparast et al., 2010; Chen and Zhou, 2013; Qian et al., 2015). Through genome-wide screening and phylogenetic analysis, it was concluded that there are 20 JmjC genes in rice and 21 JmjC genes in Arabidopsis (Sun and Zhou, 2008; Hong EH et al., 2009). JmjC proteins participate in regulating flowering time (Shi et al., 2014; Eng-Seng Gan et al., 2015). ELF6 (Early Flowering 6)/JMJ11 inhibits photoperiod-dependent flowering pathways, leading to early floral phenotypes (Noh et al., 2004). REF6/JMJ12 influences the flowering time by participating in the H3K27 methylation modification of SOC1 (Hou et al., 2014) (the main factor of the flowering pathway). JMJ14 has H3K4me3/2/l demethylase activity, and its mutants increase the expression of the flowering inhibitor FLC, thus delaying flowering time in Arabidopsis (Jeong JH et al., 2009; Lu F et al., 2011; Ning Y-Q et al., 2015; Yang et al., 2018). In addition, JMJ15 and JMJ18 have demethylase activity in H3K4, further affecting FLC transcription and regulating flowering time (Yang et al., 2012a, Yang et al., 2012b). JmjC protein also regulates the growth and gene expression in rice. OsJMJ706 can specifically remove H3K9 dimethylation and trimethylation, affecting rice flower morphology development (Sun and Zhou, 2008). OsJMJ705 can interact with WOX11 to regulate the growth and development of the tips of rice shoots(Cheng et al., 2018). Se14 (OsJMJ701) removes the H3K4me3 methylation of the FT gene and regulates flowering of rice under long days (Yokoo et al., 2014).