Biology subjects

Vey, N.

Publications and source records attributed to Vey, N..

5 recordsLinked to original sources

bioRxiv2025

Identification of AB8939, a novel synthetic microtubule destabilizer and ALDH inhibitor that overcomes multidrug resistance in tumor cells as a drug candidate for the treatment of refractory acute myeloid leukemia

We identified AB8939, a novel small synthetic molecule that exhibits strong and broad antiproliferative activity against a panel of various cancer cell types with IC50 values in the nanomolar range. In vitro investigations showed that AB8939 is a novel microtubule-targeting agent that interacts with the colchicine-binding site of tubulin. AB8939 disrupts the microtubule network, leading to mitotic arrest in G2/M phase and subsequent apoptosis. Importantly, AB8939 overcomes drug resistance mechanisms, including overexpression of efflux transporters such as P-glycoprotein (P-gp) and aberrant expression of {beta}3-tubulin. AB8939 displays high cytotoxicity against blasts from AML patients, including blasts resistant to cytarabine (Ara-C). In vivo, AB8939 shows strong antitumor activity in MOLM-14, an Ara-C-resistant AML model, as evidenced by tumor growth inhibition and substantial increase in mouse survival. Further experiments performed on an AML PDX TG-AML-36 model demonstrated that AB8939 efficiently kills leukemic stem cells (CD34+/CD38-). Reverse proteomic experiments revealed that AB8939 inhibits ALDH1 and ALDH2, enzymes often overexpressed in tumors and tumor stem cells, thereby favoring tumor progression and relapse. AB8939 is a novel dual-targeting drug that acts on both tubulin and ALDH enzymes, with potential activity against various cancer types, especially refractory AML with complex karyotypes such as those displaying MECOM rearrangement and AML with mutations associated with poor prognosis, such as ASXL1 and TP53.

cell biology↗

bioRxiv2024

Epigenenomic and transcriptomic characterization of NPM1-mutated CN-AML subtypes

Cytogenetic normal AML with NPM1 mutations forms a distinct AML entity, associated with an intermediate prognosis and a heterogeneous response to treatment. We previously described an epigenetic biomarker, defined by the level of H3K27me3 on 70kb of the HIST1 cluster in patient blast DNA. This epigenetic mark separates cytogenetically normal NPM1mut AML into two groups of patients differing in their survival rate following chemotherapy. To better characterize the influence of the biomarker on disease progression, we performed transcriptomic and histone mark profiling on patient blasts according to the level of H3K27me3 HIST1. Our integrated analysis revealed that the two groups of patients display differences in terms of transcriptomic, chromatin landscape and cell surface markers, which could explain the clinical difference. Our profiling revealed novel targets and therefore constitutes an (epi)transcriptomic resource for NPM1 AML. It also highlights the power of epigenetic profiling to dissect the heterogeneity of a single AML genetic entity.

genomics↗

bioRxiv2023

Targeting BTN2A1 enhances Vγ9Vδ2 T cell effector functions and triggers tumor cells pyroptosis

V{gamma}9V{delta}2 T cells are potent but elusive cytotoxic effectors. Means to stimulate their function could lead to powerful new cancer immunotherapies. BTN2A1, a surface protein has recently been shown to bind the V{gamma}9 chain of the {gamma}{delta} TCR but its precise role in modulating V{gamma}9V{delta}2 T cells functions remains unknown. Here we show that 107G3B5, a monoclonal anti-BTN2A1 agonist antibody, significantly enhances V{gamma}9V{delta}2 T cell functions against hematological or solid cell lines and against primary cells from adult acute lymphoblastic leukemia patients. New computer vision strategies applied to holotomographic microscopy videos show that 107G3B5 enhances the interaction between V{gamma}9V{delta}2 T cells and target cells in a quantitative and qualitative manner. In addition, we provide evidence that V{gamma}9V{delta}2 T cells activated by 107G3B5 induce caspase 3/7 activation in tumor cells, thereby triggering their death by pyroptosis. We thus demonstrate that targeting BTN2A1 with 107G3B5 enhances the V{gamma}9V{delta}2 T cell antitumor response by triggering the pyroptosis-induced immunogenic cell death.

cancer biology↗

bioRxiv2023

Downregulation of stromal syntenin sustains AML development

The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC), stromal syntenin deficiency, in turn, generating a pro-tumoral microenvironment. From serial transplantations in mice and co-culture experiments, we conclude that syntenin-deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro-tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML-stroma crosstalk and unsuspected tumor-suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy.

cancer biology↗

bioRxiv2021

A syntenin-deficient microenvironment educates AML for aggressiveness

In acute myeloid leukemia (AML), the stromal microenvironment plays a prominent role in promoting tumor cell survival and progression. Although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin, a multi-domain PDZ protein, controls both the trafficking and signaling of key molecules involved in intercellular communication. Therefore, we aimed to clarify the role of environmental syntenin in the progression of AML. By in vivo approaches in syngeneic mice, we demonstrate that a syntenin-deficient environment reprograms AML blasts to survive independently of the stroma. Up-regulation of EEF1A2 in the blasts controls this gain of cell survival. Furthermore, using ex vivo co-culture systems, we show that syntenin-deficient bone marrow stromal cells (BMSC) enhance the survival of different types of AML cells, including patient samples, and suffice to educate syngeneic AML, recapitulating micro-environmental effects observed in vivo. We establish that syntenin-deficiency causes an increase of eIF5A and autophagy-related factors in BMSC, and provide evidence that the inhibition of autophagy prevents syntenin-deficient BMSC to stimulate AML survival. Altogether, these findings indicate that host-syntenin in the BM microenvironment acts as a repressor of AML aggressiveness. Key points- A syntenin-deficient host reprograms AML blasts, enhancing total protein synthesis and cell survival pathways - Autophagy in the syntenin-deficient microenvironment is responsible for the gain of AML cell survival

cancer biology↗