Biology subjects

Gabellier, L.

Publications and source records attributed to Gabellier, L..

4 recordsLinked to original sources

bioRxiv2024

The SUMOylation inhibitor TAK-981 (Subasumstat) triggers IFN-I-dependent activation of Natural Killer cells against Acute Myeloid Leukemias.

Natural Killer (NK) cells play a pivotal role in mounting an anti-cancer immune response. Patients with diminished NK cells number and activity face less favorable prognosis. Promising therapeutic strategies include the adoptive transfer of NK cells or the reactivation of patients own NK cells. TAK-981, a first-in-class inhibitor of SUMOylation undergoing phase I/II clinical trials for cancer, is emerging as an immunomodulatory drug. Here, we demonstrate that TAK-981 activates NK cells from healthy donors and patients with Acute Myeloid Leukemia (AML), a cancer with very poor prognosis. TAK-981 heightens their degranulation capacity, secretion of inflammatory cytokines (IFN-{gamma}, TNF-, FasL), and cytotoxicity against AML cells. In vivo, TAK-981 also enhances the anti-leukemic activity of ex-vivo expanded human NK cells. At the molecular level, TAK-981 first induces IFNB1 gene in NK cells, leading to the secretion of type I Interferon (IFN-I), which binds to the Interferon receptor IFNAR. This induces Interferon-Stimulated Genes (ISG) and activates NK cells in vitro and in vivo. Finally, TAK-981 stimulates IFN-I secretion by monocytes, which contributes to the activation of NK cells in trans. Altogether, targeting SUMOylation could be a promising strategy to reactivate AML patients NK cells and enhance the efficiency of NK cells-based therapies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/580882v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1a5fd47org.highwire.dtl.DTLVardef@974336org.highwire.dtl.DTLVardef@bdb99dorg.highwire.dtl.DTLVardef@1e4fe15_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

SUMOylation controls the rapid transcriptional reprogramming induced by anthracyclines in Acute Myeloid Leukemias

Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces broad transcriptional changes in AML cells before cell death induction. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, which limits both the positive and negative effects of DNR on transcription. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Its induction is preceded by a SUMO-dependent reconfiguration of chromatin loops engaging its CTCF- and SUMO-bound promoter with distal cis-regulatory regions. Altogether, our work suggests that one of the earliest effects of DNR in AML cells is a SUMO-dependent transcriptional reprogramming.

molecular biology↗

bioRxiv2021

Discovery and mechanism of action of small molecule inhibitors of ceramidases

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes such as energy utilisation and cell proliferation. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to ultimately produce pro-proliferative sphingosine-1-phosphate. Human ceramidases can be soluble proteins (acid and neutral ceramidase) or integral membrane proteins (alkaline ceramidases). Increasing ceramide levels to increase apoptosis has shown efficacy as a cancer treatment using small molecules inhibiting a soluble ceramidase. Due to the transmembrane nature of alkaline ceramidases, no specific small molecule inhibitors have been reported. Here, we report novel fluorescent substrates (FRETceramides) of ceramidases that can be used to monitor enzyme activity in real-time. We use FRETceramides to discover the first drug-like inhibitors of alkaline ceramidase 3 (ACER3) which are active in cell-based assays. Biophysical characterization of enzyme:inhibitor interactions reveal a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules. Table of contents summaryUse of synthetic fluorescent ceramide molecules allows the discovery of the first selective drug-like small molecule inhibitors for alkaline ceramidase 3, an intra-membrane enzyme involved in sphingolipid metabolism in health and disease.

biochemistry↗

bioRxiv2021

The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of Acute Myeloid Leukemias

Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase activity, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. In addition, analyzing gp91phox (CYBB-encoded Nox2 catalytic sub-unit) expression at the surface of leukemic blasts from 74 patients at diagnosis showed that NOX2 is generally more expressed and active in leukemic cells from the FAB M4/M5 subtypes compared to FAB M0-M2 ones. Using a gene expression-based score we demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis, independent of the cytogenetic-based risk classification, in AML patients.

cancer biology↗