Publications by authors named "Blandine Roux"

5 Publications

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Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor.

Sci Transl Med 2021 Mar;13(587)

INSERM U1186, Gustave-Roussy Cancer Center, Université Paris-Saclay, 94805 Villejuif, France.

The development and survival of cancer cells require adaptive mechanisms to stress. Such adaptations can confer intrinsic vulnerabilities, enabling the selective targeting of cancer cells. Through a pooled in vivo short hairpin RNA (shRNA) screen, we identified the adenosine triphosphatase associated with diverse cellular activities (AAA-ATPase) valosin-containing protein (VCP) as a top stress-related vulnerability in acute myeloid leukemia (AML). We established that AML was the most responsive disease to chemical inhibition of VCP across a panel of 16 cancer types. The sensitivity to VCP inhibition of human AML cell lines, primary patient samples, and syngeneic and xenograft mouse models of AML was validated using -directed shRNAs, overexpression of a dominant-negative VCP mutant, and chemical inhibition. By combining mass spectrometry-based analysis of the VCP interactome and phospho-signaling studies, we determined that VCP is important for ataxia telangiectasia mutated (ATM) kinase activation and subsequent DNA repair through homologous recombination in AML. A second-generation VCP inhibitor, CB-5339, was then developed and characterized. Efficacy and safety of CB-5339 were validated in multiple AML models, including syngeneic and patient-derived xenograft murine models. We further demonstrated that combining DNA-damaging agents, such as anthracyclines, with CB-5339 treatment synergizes to impair leukemic growth in an MLL-AF9-driven AML murine model. These studies support the clinical testing of CB-5339 as a single agent or in combination with standard-of-care DNA-damaging chemotherapy for the treatment of AML.
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http://dx.doi.org/10.1126/scitranslmed.abg1168DOI Listing
March 2021

Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure.

Cancers (Basel) 2021 Feb 11;13(4). Epub 2021 Feb 11.

Université de Paris, APHP, Hôpital Saint-Louis, 75010 Paris, France.

Over the past decades, genetic advances have allowed a more precise molecular characterization of AML with the identification of novel oncogenes and tumor suppressors as part of a comprehensive AML molecular landscape. Recent advances in genetic sequencing tools also enabled a better understanding of AML leukemogenesis from the preleukemic state to posttherapy relapse. These advances resulted in direct clinical implications with the definition of molecular prognosis classifications, the development of treatment recommendations based on minimal residual disease (MRD) measurement and the discovery of novel targeted therapies, ultimately improving AML patients' overall survival. The more recent development of functional genomic studies, pushed by novel molecular biology technologies (short hairpin RNA (shRNA) and CRISPR-Cas9) and bioinformatics tools design on one hand, along with the engineering of humanized physiologically relevant animal models on the other hand, have opened a new genomics era resulting in a greater knowledge of AML physiopathology. Combining descriptive and functional genomics will undoubtedly open the road for an AML cure within the next decades.
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http://dx.doi.org/10.3390/cancers13040748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916915PMC
February 2021

Class I phosphoinositide 3-kinases control sustained NADPH oxidase activation in adherent neutrophils.

Biochem Pharmacol 2020 08 10;178:114088. Epub 2020 Jun 10.

Université Paris-Saclay, CNRS UMR 8000, Institut de Chimie Physique, 91405 Orsay, France. Electronic address:

Phagocytes, especially neutrophils, can produce reactive oxygen species (ROS), through the activation of the NADPH oxidase (NOX2). Although this enzyme is crucial for host-pathogen defense, ROS production by neutrophils can be harmful in several pathologies such as cardiovascular diseases or chronic pulmonary diseases. The ROS production by NOX2 involves the assembly of the cytosolic subunits (p67, p47, and p40) and Rac with the membrane subunits (gp91 and p22). Many studies are devoted to the activation of NOX2. However, the mechanisms that cause NADPH oxidase deactivation and thus terminate ROS production are not well known. Here we investigated the ability of class I phosphoinositide 3-kinases (PI3Ks) to sustain NADPH oxidase activation. The NADPH oxidase activation was triggered by seeding neutrophil-like PLB-985 cells, or human neutrophils on immobilized fibrinogen. Adhesion of the neutrophils, mediated by β2 integrins, induced activation of the NADPH oxidase and translocation of the cytosolic subunits at the plasma membrane. Inhibition of class I PI3Ks, and especially PI3Kβ, terminated ROS production. This deactivation of NOX2 is due to the release of the cytosolic subunits, p67 and p47 from the plasma membrane. Overexpression of an active form of Rac 1 did not prevent the drop of ROS production upon inhibition of class I PI3Ks. Moreover, the phosphorylation of p47 at S328, a potential target of kinases activated by the PI3K pathway, was unchanged. Our results indicate that the experimental downregulation of class I PI3K products triggers the plasma membrane NADPH oxidase deactivation. Release of p47 from the plasma membrane may involve its PX domains that bind PI3K products.
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http://dx.doi.org/10.1016/j.bcp.2020.114088DOI Listing
August 2020

[Hepatocarcinoma: breath or ferment].

Med Sci (Paris) 2018 12 9;34(12):1107-1109. Epub 2019 Jan 9.

Institut Curie, U1021/UMR3347, Université Paris-Saclay, 91405 Orsay, France.

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http://dx.doi.org/10.1051/medsci/2018303DOI Listing
December 2018