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Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b…

Overview of attention for article published in Journal of Hematology & Oncology, December 2016
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  • Above-average Attention Score compared to outputs of the same age (58th percentile)
  • Above-average Attention Score compared to outputs of the same age and source (62nd percentile)

Mentioned by

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3 tweeters

Citations

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49 Dimensions

Readers on

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55 Mendeley
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Title
Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b interplay
Published in
Journal of Hematology & Oncology, December 2016
DOI 10.1186/s13045-016-0362-2
Pubmed ID
Authors

Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli

Abstract

Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer. The epigenetic readers of acetylated histones bromodomain and extra-terminal (BET) proteins are critical regulators of gene expression. In cancer, they can upregulate transcription of key oncogenes such as cMYC, IRF4, and BCL-2. In addition, the activity of these proteins can regulate the expression of osteoclastogenic cytokines during cancer progression. Here, we investigated the effect of BET bromodomain protein inhibition, on the expression of NK cell-activating ligands in MM cells. Five MM cell lines [SKO-007(J3), U266, RPMI-8226, ARP-1, JJN3] and CD138(+) MM cells isolated from MM patients were used to investigate the activity of BET bromodomain inhibitors (BETi) (JQ1 and I-BET151) and of the selective BRD4-degrader proteolysis targeting chimera (PROTAC) (ARV-825), on the expression and function of several NK cell-activating ligands (NKG2DLs and DNAM-1Ls), using flow cytometry, real-time PCR, transient transfections, and degranulation assays. Our results indicate that inhibition of BET proteins via small molecule inhibitors or their degradation via a hetero-bifunctional PROTAC probe can enhance the expression of MICA, a ligand of the NKG2D receptor, in human MM cell lines and primary malignant plasma cells, rendering myeloma cells more efficient to activate NK cell degranulation. Noteworthy, similar results were obtained using selective CBP/EP300 bromodomain inhibition. Mechanistically, we found that BETi-mediated inhibition of cMYC correlates with the upregulation of miR-125b-5p and the downregulation of the cMYC/miR-125b-5p target gene IRF4, a transcriptional repressor of MICA. These findings provide new insights on the immuno-mediated antitumor activities of BETi and further elucidate the molecular mechanisms that regulate NK cell-activating ligand expression in MM.

Twitter Demographics

The data shown below were collected from the profiles of 3 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 55 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
Germany 1 2%
Unknown 53 96%

Demographic breakdown

Readers by professional status Count As %
Researcher 11 20%
Student > Master 9 16%
Student > Ph. D. Student 8 15%
Student > Bachelor 5 9%
Other 5 9%
Other 8 15%
Unknown 9 16%
Readers by discipline Count As %
Medicine and Dentistry 10 18%
Immunology and Microbiology 9 16%
Biochemistry, Genetics and Molecular Biology 8 15%
Pharmacology, Toxicology and Pharmaceutical Science 4 7%
Chemistry 4 7%
Other 8 15%
Unknown 12 22%

Attention Score in Context

This research output has an Altmetric Attention Score of 3. 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 22 June 2017.
All research outputs
#6,011,047
of 11,400,239 outputs
Outputs from Journal of Hematology & Oncology
#166
of 492 outputs
Outputs of similar age
#127,658
of 318,242 outputs
Outputs of similar age from Journal of Hematology & Oncology
#12
of 32 outputs
Altmetric has tracked 11,400,239 research outputs across all sources so far. This one is in the 46th percentile – i.e., 46% of other outputs scored the same or lower than it.
So far Altmetric has tracked 492 research outputs from this source. They receive a mean Attention Score of 3.0. This one has gotten more attention than average, scoring higher than 65% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 318,242 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 58% of its contemporaries.
We're also able to compare this research output to 32 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 62% of its contemporaries.