Gfi-1 is the transcriptional repressor of<i>SOCS1</i>in acute myeloid leukemia cells

Lee, Ming‐Cheng; Kuo, Yueh‐Hsiung; Chou, Wen‐Chien; Hou, Hsin‐An; Hsiao, Michael; Tien, Hwei‐Fang

doi:10.1189/jlb.0912475

Cited by 18 publications

(6 citation statements)

References 34 publications

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“…A previous study demonstrated that short-term treatment (8 and 16 h) of chaetocin did not alter global H3K9 tri-methylation. 27 We also found similar results (data not shown). However, long-term treatment of chaetocin indeed reduced the methylation of H3K9 and H3K27 ( Figure 3 ) indicating this drug indeed changes histone methylation status in vivo .…”

Section: Discussionsupporting

confidence: 80%

The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells

Lai

Chen

Tsai

et al. 2015

Blood Cancer Journal

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Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.

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Section: Discussionsupporting

confidence: 80%

The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells

Lai

Chen

Tsai

et al. 2015

Blood Cancer Journal

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“…Gfi1 is able to bind to a large number of promoters and enhancers (76) and plays a central role in gene silencing through the recruitment of repressive modulators including histone methyltransferases, HDACs, and histone demethylases (77–79). Gfi1 has been shown to directly interact with G9a (78, 80) and Gfi1-deficient cells display a significant decrease in H3K9 methylation (78).…”

Section: Interactions and Potential Roles Of G9amentioning

confidence: 99%

The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function

Scheer

Zaph

2017

Front. Immunol.

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G9a (KMT1C, EHMT2) is a lysine methyltransferase (KMT) whose primary function is to di-methylate lysine 9 of histone H3 (H3K9me2). G9a-dependent H3K9me2 is associated with gene silencing and acts primarily through the recruitment of H3K9me2-binding proteins that prevent transcriptional activation. Gene repression via G9a-dependent H3K9me2 is critically required in embryonic stem (ES) cells for the development of cellular lineages by repressing expression of pluripotency factors. In the immune system, lymphoid cells such as T cells and innate lymphoid cells (ILCs) can differentiate from a naïve state into one of several effector lineages that require both activating and repressive mechanisms to maintain the correct gene expression program. Furthermore, the long-term immunity to re-infection is mediated by memory T cells, which also require specific gene expression and repression to maintain a quiescent state. In this review, we examine the molecular machinery of G9a-dependent functions, address the role of G9a in lymphoid cell differentiation and function, and identify potential functions of T cells and ILCs that may be controlled by G9a. Together, this review will highlight the dynamic nature of G9a-dependent H3K9me2 in the immune system and shed light on the nature of repressive epigenetic modifications in cellular lineage choice.

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“…Chaetocin was the first reported specific S-Adenosyl-methionine (SAM)-competitive inhibitor of the histone methyltransferase SUV39H1 [27], gaining much attention since deregulated epigenetic modifiers such as histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs) have recently emerged as promising new drug targets [28]. SUV39H1 inhibition with chaetocin or RNAi-mediated SUV39H1 knockdown led to reduced tri-methylation of lysine 9 in histone 3 (H3K9me3), re-expression of silenced tumor suppressor genes and apoptosis induction in vitro and reduced tumor growth in vivo [26, 29]. Recently chaetocin has also been shown to not only reduce H3K9me3 levels, but also tri-methylation of lysine 27 in histone 3 (H3K27me3) in AML cell lines [30].…”

Section: Introductionmentioning

confidence: 99%

NT1721, a novel epidithiodiketopiperazine, exhibits potent in vitro and in vivo efficacy against acute myeloid leukemia

et al. 2016

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Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected. The IC50 values for NT1721 were significantly lower than those for clinically used AML drugs (i.e. cytarabine, sorafenib) in all tested AML cell lines regardless of their FLT3 mutation status. Moreover, combinations of NT1721 with sorafenib or cytarabine showed better antileukemic effects than the single agents in vitro. Combining cytarabine with NT1721 also attenuated the cytarabine-induced FLT3 ligand surge that has been linked to resistance to tyrosine kinase inhibitors. Mechanistically, NT1721 depleted DNA methyltransferase 1 (DNMT1) protein levels, leading to the re-expression of silenced tumor suppressor genes and apoptosis induction. NT1721 concomitantly decreased the expression of EZH2 and BMI1, two genes that are associated with the maintenance of leukemic stem/progenitor cells. In a systemic FLT3-ITD+ AML mouse model, treatment with NT1721 reduced tumor burdens by > 95% compared to the control and significantly increased survival times. Taken together, our results suggest that NT1721 may represent a promising novel agent for the treatment of AML.

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Gfi-1 is the transcriptional repressor ofSOCS1in acute myeloid leukemia cells

Cited by 18 publications

References 34 publications

The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells

The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells

The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function

NT1721, a novel epidithiodiketopiperazine, exhibits potent in vitro and in vivo efficacy against acute myeloid leukemia

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