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Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors

Overview of attention for article published in Blood, September 2011
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Title
Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors
Published in
Blood, September 2011
DOI 10.1182/blood-2011-06-363911
Pubmed ID
Authors

Paola Neri, Li Ren, Kathy Gratton, Erin Stebner, Jordan Johnson, Alexander Klimowicz, Peter Duggan, Pierfrancesco Tassone, Adnan Mansoor, Douglas A. Stewart, Sagar Lonial, Lawrence H. Boise, Nizar J. Bahlis

Abstract

Chromosomal instability is a defining feature of clonal myeloma plasma cells that results in the perpetual accumulation of genomic aberrations. In addition to its role in protein homeostasis, the ubiquitin-proteasome system is also involved in the regulation of DNA damage-repair proteins. In the present study, we show that proteasome inhibition induces a "BRCAness" state in myeloma cells (MM), with depletion of their nuclear pool of ubiquitin and abrogation of H2AX polyubiquitylation, an essential step for the recruitment of BRCA1 and RAD51 to the sites of DNA double-stranded breaks (DSBs) and the initiation of homologous recombination (HR)-mediated DNA repair. Inhibition of poly-ADP-ribose-polymerase 1 and 2 (PARP1/2) with ABT-888 induced transient DNA DSBs that were rapidly resolved and thus had no effect on viability of the MM cells. In contrast, cotreatment of MM cell lines and primary CD138(+) cells with bortezomib and ABT-888 resulted in the sustained accumulation of unrepaired DNA DSBs with persistence of unubiquitylated γH2AX foci, lack of recruitment of BRCA1 and RAD51, and ensuing MM-cell death. The heightened cytotoxicity of ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice. Our studies indicate that bortezomib impairs HR in MM and results in a contextual synthetic lethality when combined with PARP inhibitors.

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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 %
United States 1 <1%
Netherlands 1 <1%
Denmark 1 <1%
Unknown 109 97%

Demographic breakdown

Readers by professional status Count As %
Researcher 26 23%
Student > Ph. D. Student 17 15%
Student > Bachelor 7 6%
Student > Master 6 5%
Student > Doctoral Student 5 4%
Other 18 16%
Unknown 33 29%
Readers by discipline Count As %
Medicine and Dentistry 27 24%
Agricultural and Biological Sciences 25 22%
Biochemistry, Genetics and Molecular Biology 13 12%
Immunology and Microbiology 3 3%
Economics, Econometrics and Finance 3 3%
Other 8 7%
Unknown 33 29%
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 16 September 2011.
All research outputs
#17,285,036
of 25,371,288 outputs
Outputs from Blood
#27,620
of 33,239 outputs
Outputs of similar age
#97,225
of 137,154 outputs
Outputs of similar age from Blood
#239
of 305 outputs
Altmetric has tracked 25,371,288 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 33,239 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 7.6. This one is in the 12th percentile – i.e., 12% 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 137,154 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 17th percentile – i.e., 17% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 305 others from the same source and published within six weeks on either side of this one. This one is in the 8th percentile – i.e., 8% of its contemporaries scored the same or lower than it.