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    Normal and Pathological hematopoiesis

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    Team leaders

     

     

    Hematopoiesis is the biological process that allows production of all kind of blood cells. It stands all life-long. It relies on the presence of hematopoietic stem progenitor cells (HSPCs) that can be maintained as quiescent cells, can self-renew, proliferate or differentiate to generate any kind of blood cell sub-type depending on body needs. The team focuses its interests on factors that contribute to HSPC maintenance, to their commitment to produce red blood cells or megakaryocytes and platelets, and those whose dysregulation sustain leukemia and myelodysplastic syndromes in Humans.

     

     

    Hematopoiesis refers to the process leading to the continuous production of blood cells during life. In the bone marrow, it implicates rare hematopoietic stem cells capable of self-renewing and progenitors which expand and differentiate into diverse lineages. The team, with the clinical and biological departments of hematology at Cochin hospital, analyses the mechanisms responsible for stem cell maintenance, oncogenic transformation of stem and progenitor cells in myeloid leukemias and myelodysplastic syndromes and resistance to anti-leukemic drugs.

     

    Objectives

     

    Stem cell maintenance – implication of the post-transcriptional regulation of gene expression

    The basic research conducted by I Dusanter & E Lauret explores the stem cell biology in normal adult hematopoiesis and has identified two RNA binding proteins (RBP), Pumilio1/2, as key regulators of stemness. To understand the molecular mechanisms of stemness regulation, Pumilio1/2 partners and targets are investigated in the context of normal and leukemic cells. The impact of overexpressed Pumilio1/2 on gene expression profiles in leukemic cells is studied using comparative transcriptomic, proteomic, and ribosome profiling approaches.

     

    Myelodysplastic syndromes – mechanisms of oncogenic transformation

    Myelodysplastic syndromes are hematopoietic stem cell disorders with a propensity to leukemic transformation. Recurrent mutations and microenvironment interactions drive the disease initiation and clonal hematopoietic stem and progenitor cell amplification. Mechanisms underlying clonal selection are investigated using in vitro cell line models and patient-derived xenografts of hematopoietic and mesenchymal cells to immunodeficient mice (E Lauret, O Kosmider, M Fontenay).

     

    Acute myeloid leukemia – mechanisms of resistance to anti-leukemic drugs

    Important deregulation of translation and metabolic pathways has been deciphered in acute myeloid leukemia by the team leading to the proposal of targeted therapies. Large-scale screens are performed to discover intrinsic mechanisms of resistance to chemotherapy in the context of the bone marrow microenvironment. This will help deciphering new AML subgroups and identifying prognostic / theranostic biomarkers (E Lauret, N Chapuis, D Bouscary).

     

    Main Publications

    5 publications marquantes format AERES avec lien actif sur pubmed vers Hal

    (mettre l’adresse URL en bleu entre parenthèses pour faciliter le travail de mise en forme)

    dans les 5 dernières années

     

    Naudin C, Hattabi A, Michelet F, Miri-Nezhad A, Benyoucef A, Pflumio F, Guillonneau F, Fichelson S, Vigon I, Dusanter-Fourt I, Lauret E. PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells. Blood. 2017, 129:2493-2506. PMID: 28232582, PMCID: PMC5429137, DOI: 10.1182/blood-2016-10-747436

    Chesnais V, Arcangeli ML, Delette C, Rousseau A, Guermouche H, Lefevre C, Bondu S, Diop M, Cheok M, Chapuis N, Legros L, Raynaud S, Willems L, Bouscary D, Lauret E, Bernard OA, Kosmider O*, Pflumio F*, Fontenay M*. Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes. Blood. 2017; 129:484-496. PMID: 27856460, DOI: 10.1182/blood-2016-03-707745

    Poulain L, Sujobert P, Zylbersztejn F, Barreau S, Stuani L, Lambert M, Palama TL, Chesnais V, Birsen R, Vergez F, Farge T, Chenevier-Gobeaux C, Fraisse M, Bouillaud F, Debeissat C, Herault O, Récher C, Lacombe C, Fontenay M, Mayeux P, Maciel TT, Portais JC, Sarry JE, Tamburini J, Bouscary D, Chapuis N. High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells. Leukemia. 2017; 31:2326-2335. PMID: 28280275, DOI: 10.1038/leu.2017.81

    Gautier EF, Ducamp S, Leduc M, Salnot V, Guillonneau F, Dussiot M, Hale J, Giarratana MC, Raimbault A, Douay L, Lacombe C, Mohandas N, Verdier F, Zermati Y, Mayeux P. Comprehensive Proteomic Analysis of Human Erythropoiesis. Cell Rep 2016; 16: 1470-1484.

    PMID: 27452463, PMCID: PMC5274717, DOI: 10.1016/j.celrep.2016.06.085

    Sujobert P, Poulain L, Paubelle E, Zylbersztejn F, Grenier A, Lambert M, Townsend EC, Brusq JM, Nicodeme E, Decrooqc J, Nepstad I, Green AS, Mondesir J, Hospital MA, Jacque N, Christodoulou A, Desouza TA, Hermine O, Foretz M, Viollet B, Lacombe C, Mayeux P, Weinstock DM, Moura IC, Bouscary D, Tamburini J. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia. Cell Rep. 2015; 11: 1446-57. PMID: 26004183, DOI: 10.1016/j.celrep.2015.04.063

     

     

    Team’s news

     

    Labellisations

    The team is labelled by the Ligue Nationale Contre le Cancer since 2009.

    https://www.ligue-cancer.net/article/25966_les-equipes-labellisées

     

    The team is a SIRIC (site de recherche intégrée sur le cancer) CARPEM member that has been renewed in 2018 with Michaela Fontenay as a deputy director. www.carpem.fr

     

    Research project

    The team is a WP2 partner of the H2020 MDS-RIGHT project aiming at comparing existing health care interventions including methods of molecular diagnosis and at defining and implementing more effective and safer interventions for elderly European citizens with anaemia and/or lower-risk MDS, the project aims to lead to better treatment compliance and more (cost-) effective use of healthcare resources. https://mds-europe.eu/right

    Patent

    A biomarker of diagnosis and response to treatment in acquired sideroblastic anemia: INSERM-transfert EP 19305047.3 (16/01/2019)

    Meetings

    Organisation de la Journée hématologie du PRES – next 17 octobre 2019

     

     

    Contacts

    Pr Michaela Fontenay

    Bâtiment G Roussy 7è étage pièce 732

    Tel :     01 58 41 20 04

    01 40 51 64 04

     

    Pr Didier Bouscary

    Bâtiment G Roussy 7è étage pièce 732

    Tel :     01 58 41 29 46

                01 40 51 64 04