Edwige Voisset

@inserm.fr

Centre de Recherche en Cancérologie de Marseille (CRCM)
Inserm UMR1068, CNRS UMR7258, Aix-Marseille Université U105, Institut Paoli Calmettes

Edwige Voisset


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https://researchid.co/edwigevoisset
17

Scopus Publications

Scopus Publications

  • Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML
    Lise Brault, Edwige Voisset, Mathieu Desaunay, Antonia Boudet, Paraskevi Kousteridou, et al.
    EMBO Molecular Medicine, 2025
    The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.
  • The Recurrent Liver MAN2A1-FER Oncoprotein Lacks Kinase Activity: Implications for the Use of Tyrosine Kinase Inhibitors
    Mathieu Desaunay, Edwige Voisset, Sebastien Letard, Philippe Roche, Paulo De Sepulveda
    Cellular and Molecular Gastroenterology and Hepatology, 2024
  • From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia
    Magali Saez-Ayala, Laurent Hoffer, Sébastien Abel, Khaoula Ben Yaala, Benoit Sicard, et al.
    Nature Communications, 2023
    Cancer cells utilize the main de novo pathway and the alternative salvage pathway for deoxyribonucleotide biosynthesis to achieve adequate nucleotide pools. Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for anti-proliferative therapies for cancers where it is essential. Here, we present the development of a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations. This strategy allows an acceleration of the hit-to-lead process by gradually implementing key chemical modifications to increase affinity and activity. Our lead compound, OR0642, is more than 1000 times more potent than its initial parent compound, masitinib, previously identified from a drug repositioning approach. OR0642 in combination with a physiological inhibitor of the de novo pathway doubled the survival rate in a human T-cell acute lymphoblastic leukemia patient-derived xenograft mouse model, demonstrating the proof-of-concept of this drug design strategy.
  • TET2 regulates immune tolerance in chronically activated mast cells
    Riccardo Rigo, Rabie Chelbi, Julie Agopian, Sebastien Letard, Aurélien Griffon, et al.
    Jci Insight, 2022
    Mutation of the TET2 DNA-hydroxymethylase has been associated with a number of immune pathologies. The disparity in phenotype and clinical presentation among these pathologies leads to questions regarding the role of TET2 mutation in promoting disease evolution in different immune cell types. Here we show that, in primary mast cells, Tet2 expression is induced in response to chronic and acute activation signals. In TET2-deficient mast cells, chronic activation via the oncogenic KITD816V allele associated with mastocytosis, selects for a specific epigenetic signature characterized by hypermethylated DNA regions (HMR) at immune response genes. H3K27ac and transcription factor binding is consistent with priming or more open chromatin at both HMR and non-HMR in proximity to immune genes in these cells, and this signature coincides with increased pathological inflammation signals. HMR are also associated with a subset of immune genes that are direct targets of TET2 and repressed in TET2-deficient cells. Repression of these genes results in immune tolerance to acute stimulation that can be rescued with vitamin C treatment or reiterated with a Tet inhibitor. Overall, our data support a model where TET2 plays a direct role in preventing immune tolerance in chronically activated mast cells, supporting TET2 as a viable target to reprogram the innate immune response for innovative therapies.
  • Assessing BRCA1 activity in DNA damage repair using human induced pluripotent stem cells as an approach to assist classification of BRCA1 variants of uncertain significance
    Meryem Ozgencil, Julian Barwell, Marc Tischkowitz, Louise Izatt, Ian Kesterton, et al.
    Plos One, 2021
    Establishing a universally applicable protocol to assess the impact of BRCA1 variants of uncertain significance (VUS) expression is a problem which has yet to be resolved despite major progresses have been made. The numerous difficulties which must be overcome include the choices of cellular models and functional assays. We hypothesised that the use of induced pluripotent stem (iPS) cells might facilitate the standardisation of protocols for classification, and could better model the disease process. We generated eight iPS cell lines from patient samples expressing either BRCA1 pathogenic variants, non-pathogenic variants, or BRCA1 VUSs. The impact of these variants on DNA damage repair was examined using a ɣH2AX foci formation assay, a Homologous Repair (HR) reporter assay, and a chromosome abnormality assay. Finally, all lines were tested for their ability to differentiate into mammary lineages in vitro. While the results obtained from the two BRCA1 pathogenic variants were consistent with published data, some other variants exhibited differences. The most striking of these was the BRCA1 variant Y856H (classified as benign), which was unexpectedly found to present a faulty HR repair pathway, a finding linked to the presence of an additional variant in the ATM gene. Finally, all lines were able to differentiate first into mammospheres, and then into more advanced mammary lineages expressing luminal- or basal-specific markers. This study stresses that BRCA1 genetic analysis alone is insufficient to establish a reliable and functional classification for assessment of clinical risk, and that it cannot be performed without considering the other genetic aberrations which may be present in patients. The study also provides promising opportunities for elucidating the physiopathology and clinical evolution of breast cancer, by using iPS cells.
  • Src-family kinases in acute myeloid leukaemia and mastocytosis
    Edwige Voisset, Fabienne Brenet, Sophie Lopez, Paulo de Sepulveda
    Cancers, 2020
    Protein tyrosine kinases have been recognized as important actors of cell transformation and cancer progression, since their discovery as products of viral oncogenes. SRC-family kinases (SFKs) play crucial roles in normal hematopoiesis. Not surprisingly, they are hyperactivated and are essential for membrane receptor downstream signaling in hematological malignancies such as acute myeloid leukemia (AML) and mastocytosis. The precise roles of SFKs are difficult to delineate due to the number of substrates, the functional redundancy among members, and the use of tools that are not selective. Yet, a large num ber of studies have accumulated evidence to support that SFKs are rational therapeutic targets in AML and mastocytosis. These two pathologies are regulated by two related receptor tyrosine kinases, which are well known in the field of hematology: FLT3 and KIT. FLT3 is one of the most frequently mutated genes in AML, while KIT oncogenic mutations occur in 80–90% of mastocytosis. Studies on oncogenic FLT3 and KIT signaling have shed light on specific roles for members of the SFK family. This review highlights the central roles of SFKs in AML and mastocytosis, and their interconnection with FLT3 and KIT oncoproteins.
  • PML nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice
    Edwige Voisset, Eva Moravcsik, Eva W. Stratford, Amie Jaye, Christopher J. Palgrave, et al.
    Blood, 2018
    Key PointsA novel mouse model elucidates the impact of Pml NB disruption on APL pathogenesis and response to targeted therapy. The mode of action of this disruption appears to be via the perturbation of the NHEJ and HR pathways.
  • The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability
    William Grey, Adam Ivey, Thomas A. Milne, Torsten Haferlach, David Grimwade, et al.
    Biochimica Et Biophysica Acta Molecular Cell Research, 2018
  • The cryptic IRF2BP2-RARA fusion transforms hematopoietic stem/progenitor cells and induces retinoid-sensitive acute promyelocytic leukemia
    J V Jovanovic, M C Chillón, C Vincent-Fabert, R Dillon, E Voisset, et al.
    Leukemia, 2017
  • An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia
    Sophie Lopez, Edwige Voisset, Julie C. Tisserand, Cyndie Mosca, Thomas Prebet, et al.
    Oncotarget, 2016
    CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6−/− mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations.
  • KIT-D816V oncogenic activity is controlled by the juxtamembrane docking site Y568-Y570
    A Chaix, M-L Arcangeli, S Lopez, E Voisset, Y Yang, et al.
    Oncogene, 2014
  • p38α negatively regulates survival and malignant selection of transformed bronchioalveolar stem cells
    Edwige Voisset, Feride Oeztuerk-Winder, Edgar-Josue Ruiz, Juan-Jose Ventura
    Plos One, 2013
  • Mechanisms of STAT protein activation by oncogenic KIT mutants in neoplastic mast cells
    Amandine Chaix, Sophie Lopez, Edwige Voisset, Laurent Gros, Patrice Dubreuil, et al.
    Journal of Biological Chemistry, 2011
  • FES kinase participates in KIT-ligand induced chemotaxis
    Edwige Voisset, Sophie Lopez, Amandine Chaix, Marina Vita, Coralie George, et al.
    Biochemical and Biophysical Research Communications, 2010
  • FES kinases are required for oncogenic FLT3 signaling
    E Voisset, S Lopez, A Chaix, C Georges, K Hanssens, et al.
    Leukemia, 2010
  • Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT
    Patrice Dubreuil, Sébastien Letard, Marco Ciufolini, Laurent Gros, Martine Humbert, et al.
    Plos One, 2009
  • The tyrosine kinase FES is an essential effector of KITD816V proliferation signal
    Edwige Voisset, Sophie Lopez, Patrice Dubreuil, Paulo De Sepulveda
    Blood, 2007