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  1. Article ; Online: CD36 Drives Metastasis and Relapse in Acute Myeloid Leukemia.

    Farge, Thomas / Nakhle, Jean / Lagarde, Damien / Cognet, Guillaume / Polley, Nathaniel / Castellano, Rémy / Nicolau, Marie-Laure / Bosc, Claudie / Sabatier, Marie / Sahal, Ambrine / Saland, Estelle / Jeanson, Yannick / Guiraud, Nathan / Boet, Emeline / Bergoglio, Camille / Gotanègre, Mathilde / Mouchel, Pierre-Luc / Stuani, Lucille / Larrue, Clément /
    Sallese, Marie / De Mas, Véronique / Moro, Cedric / Dray, Cédric / Collette, Yves / Raymond-Letron, Isabelle / Ader, Isabelle / Récher, Christian / Sarry, Jean-Emmanuel / Cabon, Florence / Vergez, François / Carrière, Audrey

    Cancer research

    2023  Volume 83, Issue 17, Page(s) 2824–2838

    Abstract: Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and ... ...

    Abstract Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.
    Significance: CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.
    MeSH term(s) Humans ; Animals ; Mice ; Leukemia, Myeloid, Acute/pathology ; Treatment Outcome ; Prognosis ; Recurrence ; Blast Crisis/pathology ; Chronic Disease
    Language English
    Publishing date 2023-06-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-22-3682
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations.

    Sabatier, Marie / Boet, Emeline / Zaghdoudi, Sonia / Guiraud, Nathan / Hucteau, Alexis / Polley, Nathaniel / Cognet, Guillaume / Saland, Estelle / Lauture, Laura / Farge, Thomas / Sahal, Ambrine / Pancaldi, Vera / Chu-Van, Emeline / Castelli, Florence / Bertoli, Sarah / Bories, Pierre / Récher, Christian / Boutzen, Héléna / Mansat-De Mas, Véronique /
    Stuani, Lucille / Sarry, Jean-Emmanuel

    Cancers

    2021  Volume 13, Issue 20

    Abstract: Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in ... ...

    Abstract Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.
    Language English
    Publishing date 2021-10-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13205243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. 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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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6916: Show issues Location:
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  4. Article ; Online: Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.

    Stuani, Lucille / Sabatier, Marie / Saland, Estelle / Cognet, Guillaume / Poupin, Nathalie / Bosc, Claudie / Castelli, Florence A / Gales, Lara / Turtoi, Evgenia / Montersino, Camille / Farge, Thomas / Boet, Emeline / Broin, Nicolas / Larrue, Clément / Baran, Natalia / Cissé, Madi Y / Conti, Marc / Loric, Sylvain / Kaoma, Tony /
    Hucteau, Alexis / Zavoriti, Aliki / Sahal, Ambrine / Mouchel, Pierre-Luc / Gotanègre, Mathilde / Cassan, Cédric / Fernando, Laurent / Wang, Feng / Hosseini, Mohsen / Chu-Van, Emeline / Le Cam, Laurent / Carroll, Martin / Selak, Mary A / Vey, Norbert / Castellano, Rémy / Fenaille, François / Turtoi, Andrei / Cazals, Guillaume / Bories, Pierre / Gibon, Yves / Nicolay, Brandon / Ronseaux, Sébastien / Marszalek, Joseph R / Takahashi, Koichi / DiNardo, Courtney D / Konopleva, Marina / Pancaldi, Véra / Collette, Yves / Bellvert, Floriant / Jourdan, Fabien / Linares, Laetitia K / Récher, Christian / Portais, Jean-Charles / Sarry, Jean-Emmanuel

    The Journal of experimental medicine

    2021  Volume 218, Issue 5

    Abstract: Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) ... ...

    Abstract Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.
    MeSH term(s) Acute Disease ; Aminopyridines/pharmacology ; Animals ; Cell Line, Tumor ; Doxycycline/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Enzyme Inhibitors/pharmacology ; Epigenesis, Genetic/drug effects ; Glycine/analogs & derivatives ; Glycine/pharmacology ; HL-60 Cells ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors ; Isocitrate Dehydrogenase/genetics ; Isocitrate Dehydrogenase/metabolism ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Leukemia, Myeloid/drug therapy ; Leukemia, Myeloid/genetics ; Leukemia, Myeloid/metabolism ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Mitochondria/drug effects ; Mitochondria/genetics ; Mitochondria/metabolism ; Mutation ; Oxadiazoles/pharmacology ; Oxidative Phosphorylation/drug effects ; Piperidines/pharmacology ; Pyridines/pharmacology ; Triazines/pharmacology ; Xenograft Model Antitumor Assays/methods ; Mice
    Chemical Substances Aminopyridines ; Enzyme Inhibitors ; IACS-010759 ; Isoenzymes ; Oxadiazoles ; Piperidines ; Pyridines ; Triazines ; enasidenib (3T1SS4E7AG) ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; Doxycycline (N12000U13O) ; ivosidenib (Q2PCN8MAM6) ; Glycine (TE7660XO1C)
    Language English
    Publishing date 2021-03-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20200924
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.107: Show issues Location:
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    Zs.MG 45: Show issues

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  5. 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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