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    Regulators of hematopoietic stem and progenitor cells maintenance

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    Leaders :

     

    Contact :

    isabelle.dusanter@inserm.fr  Tel : +33 1 40 51 64 04

    evelyne.lauret@inserm.fr  Tel : +33 1 40 51 64 05

     

    Objectives

     

    • Identify molecular processes that regulate hematopoietic stem and progenitor cell (HSPC) maintenance
    • Determine which, and how some of these signals sustain leukemia.

     

     

     

    Hematopoietic stem cells (HSC) are quite rare cells, most commonly located in the bone marrow of adult mammalians. These cells persist whole the life-long, as quiescent cells that can reconstitute hematopoiesis at any time depending on body needs. They can self-renew, proliferate, and differentiate along all sub-types of mature functional hematopoietic cells.

    Hematopoietic stem and progenitor cell (HSPC) fate is dictated by body needs, which are mediated by blood flow and local microenvironment signals. The group wishes to identify the signaling pathways that regulate HSPC fate and those whose dysregulation contributes to onco-hemopathies. These signals should allow development of new drugs that favor stem cell amplification for cell-based therapies and/or, drugs that instead limit development of leukemic cells.

     

     

    The group

     

    The group (January 2015) includes two senior scientists (I. DF ; E. L), one junior post-doctoral scientist (C. Naudin, ARC grant), one PhD student (A. Hattabi, Paris Diderot University grant), two lab assistants (B. Izac, IE INSERM ; A. Artus, IE CDD-ANR), two Master2 students (J.El Ferekh; E. Mauro (Pierre et Marie Curie University; Paris Diderot University).

     

     

    Scientific goals

     

    Scientific projects aim at deciphering molecular mechanisms that contribute to HSPC maintenance, and those that may sustain leukemia.

    PUMILIO factors. HoxB4/C4 homeoproteins and Notch signaling pathways are essential to HSPC maintenance. We have identified genes whose expression is controlled by these factors (Auvray et al, 2013; Catelain et al, 2014), in particular PUMILIO factors.

    PUMILIOs are RNA-binding factors that work as post-transcriptional regulators to sustain stem cell maintenance in Invertebrates. We have recently shown that the two PUMILIO factors, PUMILIO-1 and PUMILIO-2 are crucial for murine and human HSPC maintenance, both in vitro and in vivo, upon hematopoietic reconstitution assays in irradiated animals.

    We are currently searching for PUMILIO mechanism of action in mammalian HSPC. Transcriptomic and global quantitative proteomic (e.g.SILAC) analyses have been both settled to identify PUMILIO targets in normal and leukemic cells. We are focusing our interest on RNA regulatory networks (function, stability, maturation, localisation…). We are analyzing PUMILIO partnerships by conventional approaches (immunoprecipitations, transcriptomics, proteomics). Also, contribution of PUMILIOs to leukemia and myelodysplastic syndromes is thoroughly studied as putative new markers or new leukemic cell growth regulators….

     

    STAT Factors. - Multiple growth factors and cytokines, and the signaling pathways they activate, contribute to HSPC maintenance and fate, and also to leukemic growth. Among these signaling pathways, we have focused our interest on STAT transducers. We have shown that STAT5 intracellular factors regulate HSPC oxidative stress, and maintenance of healthy and chronic myeloid leukemia (CML) HSPC. They further contribute to leukemic cell resistance to therapeutic treatments (Casetti et al, 2013). Also, STAT5 regulates commitment of HSPC to erythro-megakaryocytic lineages. We have identified a new form of STAT3 that is over-activated and is associated to respiratory chain complex I within mitochondria of chronic lymphoid leukemia (CLL) cells, selectively. This mitochondrial STAT3 regulates oxidative stress; it is required for CLL cell survival (Capron et al, 2014).

    We wish to identify mechanisms of action of STAT5 that contribute to HSPC fate, and can be hijacked by leukemic cells. Comparative transcriptomic and proteomic analyses have been performed to identify STAT5 targets and partners at different steps along HSPC development, and leukemic cell growth.

     

    For all our projects, both gain and loss of function studies are performed to determine the participation of any factor to hematopoiesis under normal and leukemic conditions.

     

    Recent data ; Recent publications

     

    PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells.
    Naudin C, Hattabi A, Michelet F, Miri-Nezhad A, Benyoucef A, Pflumio F, Guillonneau F, Fichelson S, Vigon I, Dusanter-Fourt I, Lauret E.
    Blood. 2017 May 4;129(18):2493-2506.

    Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes.
    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.
    Blood. 2017 Jan 26;129(4):484-496.

    CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress.
    Zhang Y, Dépond M, He L, Foudi A, Kwarteng EO, Lauret E, Plo I, Desterke C, Dessen P, Fujii N, Opolon P, Herault O, Solary E, Vainchenker W, Joulin V, Louache F, Wittner M.
    Sci Rep. 2016 Nov 25;6:37827

    Control of Pim2 kinase stability and expression in transformed human haematopoietic cells.
    Adam K, Lambert M, Lestang E, Champenois G, Dusanter-Fourt I, Tamburini J, Bouscary D, Lacombe C, Zermati Y, Mayeux P.
    Biosci Rep. 2015 Oct 23;35(6).

    Viability and stress protection of chronic lymphoid leukemia cells involves overactivation of mitochondrial phosphoSTAT3Ser727.
    Capron C, Jondeau K, Casetti L, Jalbert V, Costa C, Verhoeyen E, Massé JM, Coppo P, Béné MC, Bourdoncle P, Cramer-Bordé E, Dusanter-Fourt I.
    Cell Death Dis. 2014 Oct 9;5:e1451.  Erratum in: Cell Death Dis. 2015;6:e1627. Verhoyen, E [corrected to Verhoeyen, E].

    The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of haematopoietic progenitor cells through activation of a key gene network.
    Catelain C, Michelet F, Hattabi A, Poirault-Chassac S, Kortulewski T, Tronik-Le Roux D, Vainchenker W, Lauret E.
    Stem Cell Res. 2014 Nov;13(3 Pt A):431-41

    Differential contributions of STAT5A and STAT5B to stress protection and tyrosine kinase inhibitor resistance of chronic myeloid leukemia stem/progenitor cells.
    Casetti L, Martin-Lannerée S, Najjar I, Plo I, Augé S, Roy L, Chomel JC, Lauret E, Turhan AG, Dusanter-Fourt I.
    Cancer Res. 2013 Apr 1;73(7):2052-8.

    Notch/Delta4 signaling inhibits human megakaryocytic terminal differentiation.
    Poirault-Chassac S, Six E, Catelain C, Lavergne M, Villeval JL, Vainchenker W, Lauret E.
    Blood. 2010 Dec 16;116(25):5670-8.

     

     

    Financial supports

     
    Our research is supported by a label from « Ligue National contre le Cancer », by grants from ANR « Innovations Biomedicales », Association de Recherches contre le Cancer, Association L. Fugain, and SIRIC CARPEM.

     

    Partnerships


    Société PLATOD (www.platod.fr)