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  1. Article ; Online: RAS/RAFlandscape in monoclonal plasma cell conditions.

    Schavgoulidze, Anaïs / Corre, Jill / Samur, Mehmet K / Mazzotti, Celine / Pavageau, Luka / Perrot, Aurore / Cazaubiel, Titouan / Leleu, Xavier / Macro, Margaret / Belhadj, Karim / Roussel, Murielle / Brechignac, Sabine / Montes, Lydia / Caillot, Denis / Frenzel, Laurent / Rey, Philippe / Schiano, Jean Marc / Chalopin, Thomas / Jacquet, Caroline /
    Richez, Valentine / Orsini Piocelle, Frederique / Fontan, Jean / Manier, Salomon / Martinet, Ludovic / Sciambi, Adam / Mohty, Mohamad / Avet-Loiseau, Hervé

    Blood

    2024  

    Abstract: Multiple Myeloma (MM) is characterized by a huge heterogeneity at the molecular level. The RAS/RAF pathway is the most frequently mutated, in about 50% of the patients. However, these mutations are frequently subclonal, suggesting a secondary event. ... ...

    Abstract Multiple Myeloma (MM) is characterized by a huge heterogeneity at the molecular level. The RAS/RAF pathway is the most frequently mutated, in about 50% of the patients. However, these mutations are frequently subclonal, suggesting a secondary event. Since these genes are part of our routine next-generation sequencing (NGS) panel, we analyzed >10,000 patients with different plasma cell disorders in order to describe the RAS/RAF landscape. In this large cohort of patients, almost 61% of the patients presented a RAS/RAF mutation at diagnosis or relapse, but much lower frequencies in pre-symptomatic cases. Of note, the mutations were different from that observed in solid tumors (higher proportions of Q61 mutations). In 29 patients with two different mutations, we were able to perform single cell sequencing, showing that in most cases, mutations occurred in different subclones, suggesting an ongoing mutational process. These findings suggest that RAS/RAF pathway is not an attractive target, both on therapeutic and residual disease assessment points of vue.
    Language English
    Publishing date 2024-04-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2023022295
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present From Diagnosis in Tiny, Undetectable Subclonal Populations.

    Lannes, Romain / Samur, Mehmet / Perrot, Aurore / Mazzotti, Celine / Divoux, Marion / Cazaubiel, Titouan / Leleu, Xavier / Schavgoulidze, Anaïs / Chretien, Marie-Lorraine / Manier, Salomon / Adiko, Didier / Orsini-Piocelle, Frederique / Lifermann, François / Brechignac, Sabine / Gastaud, Lauris / Bouscary, Didier / Macro, Margaret / Cleynen, Alice / Mohty, Mohamad /
    Munshi, Nikhil / Corre, Jill / Avet-Loiseau, Hervé

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology

    2022  Volume 41, Issue 9, Page(s) 1695–1702

    Abstract: Purpose: Multiple myeloma (MM) is characterized by copy number abnormalities (CNAs), some of which influence patient outcomes and are sometimes observed only at relapse(s), suggesting their acquisition during tumor evolution. However, the presence of ... ...

    Abstract Purpose: Multiple myeloma (MM) is characterized by copy number abnormalities (CNAs), some of which influence patient outcomes and are sometimes observed only at relapse(s), suggesting their acquisition during tumor evolution. However, the presence of micro-subclones may be missed in bulk analyses. Here, we use single-cell genomics to determine how often these high-risk events are missed at diagnosis and selected at relapse.
    Materials and methods: We analyzed 81 patients with plasma cell dyscrasias using single-cell CNA sequencing. Sixty-six patients were selected at diagnosis, nine at first relapse, and six in presymptomatic stages. A total of 956 newly diagnosed patients with MM and patients with first relapse MM have been identified retrospectively with required cytogenetic data to evaluate enrichment of CNA risk events and survival impact.
    Results: A total of 52,176 MM cells were analyzed. Seventy-four patients (91%) had 2-16 subclones. Among these patients, 28.7% had a subclone with high-risk features (del(17p), del(1p32), and 1q gain) at diagnosis. In a patient with a subclonal 1q gain at diagnosis, we analyzed the diagnosis, postinduction, and first relapse samples, which showed a rise of the high-risk 1q gain subclone (16%, 70%, and 92%, respectively). In our clinical database, we found that the 1q gain frequency increased from 30.2% at diagnosis to 43.6% at relapse (odds ratio, 1.78; 95% CI, 1.58 to 2.00). We subsequently performed survival analyses, which showed that the progression-free and overall survival curves were superimposable between patients who had the 1q gain from diagnosis and those who seemingly acquired it at relapse. This strongly suggests that many patients had 1q gains at diagnosis in microclones that were missed by bulk analyses.
    Conclusion: These data suggest that identifying these scarce aggressive cells may necessitate more aggressive treatment as early as diagnosis to prevent them from becoming the dominant clone.
    MeSH term(s) Humans ; Multiple Myeloma/diagnosis ; Multiple Myeloma/genetics ; Multiple Myeloma/therapy ; Retrospective Studies ; Neoplasm Recurrence, Local/genetics ; Prognosis ; Survival Analysis ; Chromosome Aberrations
    Language English
    Publishing date 2022-11-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604914-x
    ISSN 1527-7755 ; 0732-183X
    ISSN (online) 1527-7755
    ISSN 0732-183X
    DOI 10.1200/JCO.21.01987
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: TCR-independent CD137 (4-1BB) signaling promotes CD8

    Pichler, Andrea C / Carrié, Nadège / Cuisinier, Marine / Ghazali, Samira / Voisin, Allison / Axisa, Pierre-Paul / Tosolini, Marie / Mazzotti, Céline / Golec, Dominic P / Maheo, Sabrina / do Souto, Laura / Ekren, Rüçhan / Blanquart, Eve / Lemaitre, Lea / Feliu, Virginie / Joubert, Marie-Véronique / Cannons, Jennifer L / Guillerey, Camille / Avet-Loiseau, Hervé /
    Watts, Tania H / Salomon, Benoit L / Joffre, Olivier / Grinberg-Bleyer, Yenkel / Schwartzberg, Pamela L / Lucca, Liliana E / Martinet, Ludovic

    Immunity

    2023  Volume 56, Issue 7, Page(s) 1631–1648.e10

    Abstract: CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we ... ...

    Abstract CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8
    MeSH term(s) Mice ; Animals ; CD8-Positive T-Lymphocytes ; Tumor Necrosis Factor Receptor Superfamily, Member 9 ; Neoplasms ; Cell Differentiation ; Cell Proliferation ; Receptors, Antigen, T-Cell
    Chemical Substances Tumor Necrosis Factor Receptor Superfamily, Member 9 ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2023-06-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2023.06.007
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  4. Article ; Online: Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow.

    Mazzotti, Céline / Buisson, Laure / Maheo, Sabrina / Perrot, Aurore / Chretien, Marie-Lorraine / Leleu, Xavier / Hulin, Cyrille / Manier, Salomon / Hébraud, Benjamin / Roussel, Murielle / Do Souto, Laura / Attal, Michel / Avet-Loiseau, Hervé / Corre, Jill

    Blood advances

    2018  Volume 2, Issue 21, Page(s) 2811–2813

    MeSH term(s) Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Bone Marrow/metabolism ; Circulating Tumor DNA/chemistry ; Circulating Tumor DNA/metabolism ; High-Throughput Nucleotide Sequencing ; Humans ; Multiple Myeloma/diagnosis ; Multiple Myeloma/metabolism ; Neoplasm, Residual ; Plasma Cells/metabolism ; Sequence Analysis, DNA ; V(D)J Recombination/genetics
    Chemical Substances Biomarkers, Tumor ; Circulating Tumor DNA
    Language English
    Publishing date 2018-10-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2876449-3
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2018025197
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress-Induced Ferroptosis in FLT3-Mutant Leukemia.

    Sabatier, Marie / Birsen, Rudy / Lauture, Laura / Mouche, Sarah / Angelino, Paolo / Dehairs, Jonas / Goupille, Léa / Boussaid, Ismael / Heiblig, Maël / Boet, Emeline / Sahal, Ambrine / Saland, Estelle / Santos, Juliana C / Armengol, Marc / Fernández-Serrano, Miranda / Farge, Thomas / Cognet, Guillaume / Simonetta, Federico / Pignon, Corentin /
    Graffeuil, Antoine / Mazzotti, Céline / Avet-Loiseau, Hervé / Delos, Océane / Bertrand-Michel, Justine / Chedru, Amélie / Dembitz, Vilma / Gallipoli, Paolo / Anstee, Natasha S / Loo, Sun / Wei, Andrew H / Carroll, Martin / Goubard, Armelle / Castellano, Rémy / Collette, Yves / Vergez, François / Mansat-De Mas, Véronique / Bertoli, Sarah / Tavitian, Suzanne / Picard, Muriel / Récher, Christian / Bourges-Abella, Nathalie / Granat, Fanny / Kosmider, Olivier / Sujobert, Pierre / Colsch, Benoit / Joffre, Carine / Stuani, Lucille / Swinnen, Johannes V / Guillou, Hervé / Roué, Gael / Hakim, Nawad / Dejean, Anne S / Tsantoulis, Petros / Larrue, Clément / Bouscary, Didier / Tamburini, Jerome / Sarry, Jean-Emmanuel

    Cancer discovery

    2023  Volume 13, Issue 7, Page(s) 1720–1747

    Abstract: Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated ... ...

    Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)-stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.
    Significance: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501.
    MeSH term(s) Humans ; CCAAT-Enhancer-Binding Protein-alpha/genetics ; CCAAT-Enhancer-Binding Protein-alpha/metabolism ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/metabolism ; Ferroptosis ; Fatty Acids ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mutation ; Oxidative Stress ; Protein Kinase Inhibitors/therapeutic use ; Cell Line, Tumor
    Chemical Substances CCAAT-Enhancer-Binding Protein-alpha ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; Fatty Acids ; Protein Kinase Inhibitors ; FLT3 protein, human (EC 2.7.10.1)
    Language English
    Publishing date 2023-04-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-22-0411
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6916: Show issues Location:
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  6. Article ; Online: Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia.

    Bosc, Claudie / Saland, Estelle / Bousard, Aurélie / Gadaud, Noémie / Sabatier, Marie / Cognet, Guillaume / Farge, Thomas / Boet, Emeline / Gotanègre, Mathilde / Aroua, Nesrine / Mouchel, Pierre-Luc / Polley, Nathaniel / Larrue, Clément / Kaphan, Eléonore / Picard, Muriel / Sahal, Ambrine / Jarrou, Latifa / Tosolini, Marie / Rambow, Florian /
    Cabon, Florence / Nicot, Nathalie / Poillet-Perez, Laura / Wang, Yujue / Su, Xiaoyang / Fovez, Quentin / Kluza, Jérôme / Argüello, Rafael José / Mazzotti, Céline / Avet-Loiseau, Hervé / Vergez, François / Tamburini, Jérôme / Fournié, Jean-Jacques / Tiong, Ing S / Wei, Andrew H / Kaoma, Tony / Marine, Jean-Christophe / Récher, Christian / Stuani, Lucille / Joffre, Carine / Sarry, Jean-Emmanuel

    Nature cancer

    2021  Volume 2, Issue 11, Page(s) 1204–1223

    Abstract: Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with ... ...

    Abstract Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.
    MeSH term(s) Azacitidine/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cytarabine/pharmacology ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Sulfonamides
    Chemical Substances Bridged Bicyclo Compounds, Heterocyclic ; Sulfonamides ; Cytarabine (04079A1RDZ) ; Azacitidine (M801H13NRU) ; venetoclax (N54AIC43PW)
    Language English
    Publishing date 2021-11-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2662-1347
    ISSN (online) 2662-1347
    DOI 10.1038/s43018-021-00264-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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