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RNA Polymerase I Inhibition with CX‐5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma

Overview of attention for article published in British Journal of Haematology, March 2017
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Title
RNA Polymerase I Inhibition with CX‐5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma
Published in
British Journal of Haematology, March 2017
DOI 10.1111/bjh.14525
Pubmed ID
Authors

Hans C. Lee, Hua Wang, Veerabhadran Baladandayuthapani, Heather Lin, Jin He, Richard J. Jones, Isere Kuiatse, Dongmin Gu, Zhiqiang Wang, Wencai Ma, John Lim, Sean O'Brien, Jonathan Keats, Jing Yang, Richard E. Davis, Robert Z. Orlowski

Abstract

Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis. Moreover, Pol I inhibition overcame adhesion-mediated drug resistance and resistance to conventional and novel agents. To probe the TP53-independent mechanisms of CX-5461, gene expression profiling was performed on isogenic TP53 WT and knockout cell lines and revealed reduction of MYC downstream targets. Mechanistic studies confirmed that CX-5461 rapidly suppressed both MYC protein and MYC mRNA levels. The latter was associated with an increased binding of the RNA-induced silencing complex (RISC) subunits TARBP2 and AGO2, the ribosomal protein RPL5, and MYC mRNA, resulting in increased MYC transcript degradation. Collectively, these studies provide a rationale for the clinical translation of CX-5461 as a novel therapeutic approach to target MYC in myeloma.

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X Demographics

The data shown below were collected from the profiles of 2 X users 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 68 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 1%
Unknown 67 99%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 11 16%
Student > Master 9 13%
Researcher 8 12%
Student > Bachelor 8 12%
Student > Doctoral Student 5 7%
Other 13 19%
Unknown 14 21%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 25 37%
Medicine and Dentistry 10 15%
Agricultural and Biological Sciences 7 10%
Pharmacology, Toxicology and Pharmaceutical Science 4 6%
Nursing and Health Professions 2 3%
Other 3 4%
Unknown 17 25%
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 09 June 2017.
All research outputs
#16,699,002
of 24,561,012 outputs
Outputs from British Journal of Haematology
#6,103
of 7,910 outputs
Outputs of similar age
#199,439
of 312,947 outputs
Outputs of similar age from British Journal of Haematology
#92
of 142 outputs
Altmetric has tracked 24,561,012 research outputs across all sources so far. This one is in the 21st percentile – i.e., 21% of other outputs scored the same or lower than it.
So far Altmetric has tracked 7,910 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.7. This one is in the 16th percentile – i.e., 16% of its peers scored the same or lower than it.
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 312,947 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 27th percentile – i.e., 27% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 142 others from the same source and published within six weeks on either side of this one. This one is in the 22nd percentile – i.e., 22% of its contemporaries scored the same or lower than it.