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Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma

Overview of attention for article published in Hematology Journal, June 2018
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Title
Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma
Published in
Hematology Journal, June 2018
DOI 10.3324/haematol.2017.180505
Pubmed ID
Authors

Clara Recasens-Zorzo, Teresa Cardesa-Salzmann, Paolo Petazzi, Laia Ros-Blanco, Anna Esteve-Arenys, Guillem Clot, Martina Guerrero-Hernández, Vanina Rodríguez, Davide Soldini, Alexandra Valera, Alexandra Moros, Fina Climent, Eva González-Barca, Santiago Mercadal, Leonor Arenillas, Xavier Calvo, José Luís Mate, Gonzalo Gutiérrez-García, Isolda Casanova, Ramón Mangues, Alejandra Sanjuan-Pla, Clara Bueno, Pablo Menéndez, Antonio Martínez, Dolors Colomer, Roger Estrada Tejedor, Jordi Teixidó, Elias Campo, Armando López-Guillermo, José Ignacio Borrell, Luis Colomo, Patricia Pérez-Galán, Gaël Roué

Abstract

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous cohort of 52 patient biopsies, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing to a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, IQS-01.01RS/CPI203 combination decreased tumor burden through MYC and p-AKT downregulation, and enhanced apoptosis induction. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for this disease.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 47 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 47 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 10 21%
Student > Bachelor 7 15%
Student > Master 5 11%
Professor > Associate Professor 4 9%
Student > Ph. D. Student 3 6%
Other 7 15%
Unknown 11 23%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 17 36%
Chemistry 5 11%
Medicine and Dentistry 5 11%
Pharmacology, Toxicology and Pharmaceutical Science 3 6%
Agricultural and Biological Sciences 2 4%
Other 3 6%
Unknown 12 26%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 4. 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 28 June 2018.
All research outputs
#8,497,985
of 26,161,782 outputs
Outputs from Hematology Journal
#1,796
of 4,207 outputs
Outputs of similar age
#133,344
of 345,983 outputs
Outputs of similar age from Hematology Journal
#51
of 100 outputs
Altmetric has tracked 26,161,782 research outputs across all sources so far. This one has received more attention than most of these and is in the 67th percentile.
So far Altmetric has tracked 4,207 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.6. This one has gotten more attention than average, scoring higher than 56% 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 345,983 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 61% of its contemporaries.
We're also able to compare this research output to 100 others from the same source and published within six weeks on either side of this one. This one is in the 49th percentile – i.e., 49% of its contemporaries scored the same or lower than it.