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The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation

Overview of attention for article published in Cell Communication and Signaling, March 2017
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Title
The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation
Published in
Cell Communication and Signaling, March 2017
DOI 10.1186/s12964-017-0168-z
Pubmed ID
Authors

Florian Wolff, Michael Leisch, Richard Greil, Angela Risch, Lisa Pleyer

Abstract

Hypomethylating agents (HMAs) have been widely used over the last decade, approved for use in myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The proposed central mechanism of action of HMAs, is the reversal of aberrant methylation in tumor cells, thus reactivating CpG-island promoters and leading to (re)expression of tumor suppressor genes. Recent investigations into the mode of action of azacitidine (AZA) and decitabine (DAC) have revealed new molecular mechanisms that impinge on tumor immunity via induction of an interferon response, through activation of endogenous retroviral elements (ERVs) that are normally epigenetically silenced. Although the global demethylation of DNA by HMAs can induce anti-tumor effects, it can also upregulate the expression of inhibitory immune checkpoint receptors and their ligands, resulting in secondary resistance to HMAs. Recent studies have, however, suggested that this could be exploited to prime or (re)sensitize tumors to immune checkpoint inhibitor therapies. In recent years, immune checkpoints have been targeted by novel therapies, with the aim of (re)activating the host immune system to specifically eliminate malignant cells. Antibodies blocking checkpoint receptors have been FDA-approved for some solid tumors and a plethora of clinical trials testing these and other checkpoint inhibitors are under way. This review will discuss AZA and DAC novel mechanisms of action resulting from the re-expression of pathologically hypermethylated promoters of gene sets that are related to interferon signaling, antigen presentation and inflammation. We also review new insights into the molecular mechanisms of action of transient, low-dose HMAs on various tumor types and discuss the potential of new treatment options and combinations.

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The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 112 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Netherlands 1 <1%
Unknown 111 99%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 30 27%
Researcher 24 21%
Student > Bachelor 12 11%
Student > Master 9 8%
Student > Doctoral Student 5 4%
Other 12 11%
Unknown 20 18%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 27 24%
Medicine and Dentistry 26 23%
Agricultural and Biological Sciences 15 13%
Pharmacology, Toxicology and Pharmaceutical Science 6 5%
Immunology and Microbiology 4 4%
Other 11 10%
Unknown 23 21%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 12 April 2017.
All research outputs
#19,594,120
of 24,093,053 outputs
Outputs from Cell Communication and Signaling
#787
of 1,162 outputs
Outputs of similar age
#240,569
of 312,831 outputs
Outputs of similar age from Cell Communication and Signaling
#6
of 6 outputs
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So far Altmetric has tracked 1,162 research outputs from this source. They receive a mean Attention Score of 3.8. This one is in the 8th percentile – i.e., 8% of its peers scored the same or lower than it.
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We're also able to compare this research output to 6 others from the same source and published within six weeks on either side of this one.