The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

Duque‐Afonso, Jesús; Yalcin, Arzu; Berg, Tobias; Abdelkarim, Mahmoud; Heidenreich, Olaf; Lübbert, Michael

doi:10.1038/onc.2011.32

Cited by 45 publications

(34 citation statements)

References 52 publications

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“…In agreement with these results, a recent paper demonstrated that mocetinostat and entinostat, but not TSA or sodium valproate, increased the expression of LAT2, which is a target of AML1-ETO. 32 Our results raise the possibility that treatment with certain HDACi may be effective in AML patients bearing these fusion proteins. Such treatment can be combined with ATRA in case of acute promyelocytic leukemia (the AML type that is associated with PML-RARA), especially because we found that ATRA alone does not reverse the downregulation of CD48.…”

Section: Discussionmentioning

confidence: 66%

“…32 Importantly, the predicted sequence of the binding site of AML1-ETO in the CD48 gene, as well as LAT2, were significantly enriched both with the anti-ETO and the anti-AML1-ETO antibodies compared with the control anti-HA mAb and to the unrelated site ( Figure 6G). These experiments verify that indeed, AML1-ETO binds directly to the CD48 gene.…”

Section: 49mentioning

confidence: 96%

“…Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. mocetinostat (MGCD0103, catalog #S1122, Selleck Chemicals) dissolved in dimethyl sulfoxide at a final concentration of 1 mM for 18 to 24 hours, as previously described 32 ; valproic acid (P4543, Sigma-Aldrich) dissolved in water at a final concentration of 5 mM for 24 hours; entinostat (MS-275, catalog #27011; BPS Bioscience) dissolved in dimethyl sulfoxide at a final concentration of 1 mM for 18 to 24 hours, as previously described. 32 We also used all-trans-retinoic acid (ATRA) (retinoic acid, catalog #R2625; Sigma-Aldrich) dissolved in dimethyl sulfoxide at a final concentration of 10 mM for 72 hours.…”

Section: Drugsmentioning

confidence: 99%

“…32 We also used all-trans-retinoic acid (ATRA) (retinoic acid, catalog #R2625; Sigma-Aldrich) dissolved in dimethyl sulfoxide at a final concentration of 10 mM for 72 hours.…”

mentioning

confidence: 99%

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Immune evasion by oncogenic proteins of acute myeloid leukemia

Elias¹,

Yamin²,

Golomb

et al. 2014

Blood

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Key Points• PML-RARA and AML1-ETO evade NK cell recognition by specifically downregulating the expression of CD48.• The findings are relevant to AML patients bearing these specific translocations.PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Whether these fusion proteins render the tumor cells with immune evasion properties is unknown. Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells. We demonstrate that this process is histone deacetylase (HDAC)-dependent, that it is mediated through the downregulation of CD48 messenger RNA, and that treatment with HDAC inhibitors (HDACi) restores the expression of CD48. Furthermore, by using chromatin immuoprecepitation (ChIP) experiments, we show that AML1-ETO directly interacts with CD48. Finally, we show that AML patients who are carrying these specific translocations have low expression of CD48. (Blood. 2014;123(10):1535-1543 Introduction Acute myeloid leukemia (AML) is the most common acute leukemia in adults. 1 There are several types of AML (approximately 30%) that are characterized by chromosomal translocations, which generate oncogenic fusion proteins.2 Two of the most common translocations in AML are t(15:17), which gives rise to the fusion protein PML-RARA, and t(8:21), which generates the fusion protein RUNX1-RUNX1T1 (AML1-ETO).3,4 Although these fusion proteins were discovered more than 20 years ago, 5,6 it is not known whether they provide immune evasion properties to AML tumors.Over the past few decades it has been established that natural killer (NK) cells, which are part of the innate immune system, play an important role in killing cancerous cells, 7,8 and specifically AML cells. 9,10 Several studies have found that AML patients who received transplants from NK alloreactive donors had lower relapse rates and improved disease-free survival. [11][12][13] Furthermore, it was recently reported that the presence of the NK cell receptor KIR2DS1, in matched unrelated donors, is associated with distinct outcomes of allogeneic hematopoietic stem cell transplantation in AML patients. 14 Finally, it was shown in several studies that NK cell activity correlates with clinical parameters of AML patients. 15,16 Killing by NK cells is mediated by several killer receptors that recognize distinct ligands. [17][18][19][20][21][22][23][24] Several human killer receptors, such as NKp44 and NKp30, have no mouse orthologs, and others, such as 2B4, have a mouse ortholog protein with opposing functions. In humans, 2B4 functions as an activating receptor, [25][26][27] whereas in mice, it mainly functions as an inhibitory receptor. 28,29 However, in both cases it recognizes CD48. [25][26][27][28] Despite the crucial role played by NK cells in eliminating AML tumors, the NK cell recognition of AML tumor cells is impaired at several levels (r...

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Section: Discussionmentioning

confidence: 66%

Section: 49mentioning

confidence: 96%

Section: Drugsmentioning

confidence: 99%

“…32 We also used all-trans-retinoic acid (ATRA) (retinoic acid, catalog #R2625; Sigma-Aldrich) dissolved in dimethyl sulfoxide at a final concentration of 10 mM for 72 hours.…”

mentioning

confidence: 99%

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Immune evasion by oncogenic proteins of acute myeloid leukemia

Elias¹,

Yamin²,

Golomb

et al. 2014

Blood

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“…On the basis of our analysis, we propose a model of interactions (Fig. 4) based on both previous data (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and the interactions we found. This example provides evidence that our approach has identified "-omic" linkages that, although new, have basis in biochemical rationale and are supported, in part, by past research (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Systems Analysis of the NCI-60 Cancer Cell Lines by Alignment of Protein Pathway Activation Modules with “-OMIC” Data Fields and Therapeutic Response Signatures

Federici

Gao

Slawek

et al. 2013

Molecular Cancer Research

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The NCI-60 cell line set is likely the most molecularly profiled set of human tumor cell lines in the world. However, a critical missing component of previous analyses has been the inability to place the massive amounts of "-omic" data in the context of functional protein signaling networks, which often contain many of the drug targets for new targeted therapeutics. We used reverse-phase protein array (RPPA) analysis to measure the activation/ phosphorylation state of 135 proteins, with a total analysis of nearly 200 key protein isoforms involved in cell proliferation, survival, migration, adhesion, etc., in all 60 cell lines. We aggregated the signaling data into biochemical modules of interconnected kinase substrates for 6 key cancer signaling pathways: AKT, mTOR, EGF receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), integrin, and apoptosis signaling. The net activation state of these protein network modules was correlated to available individual protein, phosphoprotein, mutational, metabolomic, miRNA, transcriptional, and drug sensitivity data. Pathway activation mapping identified reproducible and distinct signaling cohorts that transcended organ-type distinctions. Direct correlations with the protein network modules involved largely protein phosphorylation data but we also identified direct correlations of signaling networks with metabolites, miRNA, and DNA data.

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The histone deacetylase inhibitor Entinostat enhances polymer‐mediated transgene expression in cancer cell lines

Elmer

Christensen

Barua

et al. 2015

Biotech & Bioengineering

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Eukaryotic cells maintain an immense amount of genetic information by tightly wrapping their DNA around positively charged histones. While this strategy allows human cells to maintain more than 25,000 genes, histone binding can also block gene expression. Consequently, cells express histone acetyl transferases (HATs) to acetylate histone lysines and release DNA for transcription. Conversely, histone deacetylases (HDACs) are employed for restoring the positive charge on the histones, thereby silencing gene expression by increasing histone-DNA binding. It has previously been shown that histones bind and silence viral DNA, while hyperacetylation of histones via HDAC inhibition restores viral gene expression. In this study, we demonstrate that treatment with Entinostat, an HDAC inhibitor, enhances transgene (luciferase) expression by up to 25-fold in human prostate and murine bladder cancer cell lines when used with cationic polymers for plasmid DNA delivery. Entinostat treatment altered cell cycle progression, resulting in a significant increase in the fraction of cells present in the G0/G1 phase at low micromolar concentrations. While this moderate G0/G1 arrest disappeared at higher concentrations, a modest increase in the fraction of apoptotic cells and a decrease in cell proliferation were observed, consistent with the known anticancer effects of the drug. DNase accessibility studies revealed no significant change in plasmid transcriptional availability with Entinostat treatment. However, quantitative PCR studies indicated that Entinostat treatment, at the optimal dose for enhancing transgene expression, led to an increase in the amount of plasmid present in the nucleus in two cancer cell lines. Taken together, our results show that Entinostat enhances polymer-mediated transgene expression and can be useful in applications related to transient protein expression in mammalian cells.

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The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

Cited by 45 publications

References 52 publications

Immune evasion by oncogenic proteins of acute myeloid leukemia

Immune evasion by oncogenic proteins of acute myeloid leukemia

Systems Analysis of the NCI-60 Cancer Cell Lines by Alignment of Protein Pathway Activation Modules with “-OMIC” Data Fields and Therapeutic Response Signatures

The histone deacetylase inhibitor Entinostat enhances polymer‐mediated transgene expression in cancer cell lines

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