Bienvenu(e) sur le site de l'Institut Necker Enfants Malades

Compréhension de l'arrêt de maturation oncogénique afin d'identifier des thérapies différentiantes spécifiques

de la science fondamentale :
  • dérégulation de la lymphopoïèse T humaine
à la recherche translationnelle :
  • leucémie
  • lymphome
Elizabeth Macintyre
Vahid Asnafi
Différentiation lymphoïde normale et pathologique

Elizabeth Macintyre, M.D-PhD FRCP/Path is Professor of Hematology at the Paris Descartes Medical School. She trained in internal Medicine and clinical and laboratory Hematology in the UK (Newcastle and UCL), did her PhD in Paris (St. Louis) and her post-doctoral fellowship in Harvard. She joined the Medical Faculty at Descartes in 1992 and has headed the Hematology Laboratory and the integrated Hematopathology Cancer programmes since 1999 and 2007, respectively.

Vahid Asnafi, M.D-PhD studied Medicine at Paris Descartes before specializing in laboratory Hematology. He obtained his PhD at Descartes in 2003 before doing his post-doctoral studies with Pierre Ferrier at CIML, Marseille. Returning to Necker in 2005, he was appointed full Professor of Hematology in 2012 and now heads the Onco-Hématology laboratory and well as co-directing the "Normal and Pathological Lymphoid Differentiation Team" at INEM

Focus

We study molecular mechanisms controlling TCR VDJ rearrangements during human T-cell ontogeny and their implication in (epi)genetic deregulation in T-lymphoid oncogenesis, in order to develop targeted therapeutics for leukemia and lymphoma.

Introduction

Our research essentially involves analysis of the mechanisms controlling human T lymphoid ontogeny and oncogenic transformation in immature T lymphoid malignancies, particularly T-cell lymphoblastic acute leukemias (T-ALL) and lymphomas (T-LBL).

T-ALLs are malignant clonal proliferations arrested at specific stages of thymic differentiation. Oncogenic deregulation and physiological T lymphopoiesis, including the mechanisms regulating the somatic rearrangements leading to assembly of a T Cell Receptor (TCR), are intimately linked, which implies the contribution of physiological proliferative/apoptotic signals to the oncogenic process.

We have developed cellular and molecular characterisation of lymphoid malignancies in close collaboration with clinical cooperative and fundamental cognitive research groups in order to ensure optimal human tissue resource management and valorisation. All research projects are based on the principal that unravelling oncogenic pathways with an aim to improving treatment requires in-depth understanding of normal development of the system which has undergone deregulated tissue homeostasis.

These studies are possible due to close collaboration with the adult (Group for Research in Adult ALL or GRAALL and Lymphoma Study Association or LYSA) and pediatric (Société Française des Cancers de l’Enfant or SFCE Leukemia and Lymphoma committees) clinical cooperative groups, and with a variety of European networks, such as the EuroFLOW, EuroMRD, EuroClonality and Blueprint consortia.

Research objectives

Cellular and molecular characterization of lymphoid malignancies, with particular emphasis on T lymphoid oncogenesis:

  1. Read the language of antigen receptor (Immunoglobulin and T Cell Receptor) rearrangements in order to:
    • understand maturation arrest and lineage affiliation in order to improve classification of lymphoid malignancies
    • explore the potential oncogenic role of deregulated receptor rearrangements in the development of lymphoid malignancies
    • analyse TCR signalling function in T lymphoid oncogenesis
    • identify the potential for therapeutic correction of blocked lymphoid maturation secondary to deregulated receptor rearrangement
    • explore the mechanisms of action of Homeotic proteins during normal and pathological thymopoiesis
    • Explore the epigenetic regulation of human VDJ rearrangements during T lymphoid development (Blueprint)
  2. Explore Immature T/My/NK/ILC disorders in order to explore the interface between the lymphoid and myeloid lineages
  3. Study the Role of cytokine receptors, NOTCH1/FBXW7 pathway deregulation and aberrant signalling pathways in T-lymphoid oncogenesis
  4. Use innovative cellular and molecular techniques in order to improve integrated management of patients with leukaemia and lymphoma at diagnosis and follow-up, with particular emphasis on:
    • Ig/TCR markers for minimal residual disease personalized management in ALL and NHL
    • Multiparameter flow cytometry
    • Digital droplet quantification
    • High-throughput somatic onco- and immuno-genetics at diagnosis and follow-up

5 main publications

  • Trinquand A et al. (2016) Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia. Cancer Discov. Sep;6(9):972-85
  • Malcolm et al. (2016) NPM-ALK mimics thymic pre-TCR expansion requiring transient TCR expression for thymic egress and peripheral ALCL Nature Communications. 7:10087
  • Cieslak A et al. (2014) RUNX1 dependent RAG1 deposition instigates Human TCRα locus rearrangement. J Exp Med. Aug 25;211(9):1821-32
  • Trinquand A. et al. (2013) Towards a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-ALL: a GRAALL Study. Journal of clinical oncology Dec 1;31(34):4333-42
  • Dadi S et al. TLX homeodomain oncogenes mediate T-cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCRα gene expression. Cancer Cell. Apr 17;21(4):563-76
30 dernières publications

2017

  • Cordonnier G, Mandoli A, Radhouane A, Hypolite G, Lhermitte L, Belhocine M, Asnafi V, Macintyre E, Martens JH, Fumagalli S, Bond J. Letter to the Editor: CBFβ-SMMHC regulates ribosomal gene transcription and alters ribosome biogenesis. Leukemia. 2017 Feb 15. doi: 10.1038/leu.2017.53. [Epub ahead of print]
  • Costa C, Hypolite G, Bernadin O, Lévy C, Cosset FL, Asnafi V, Macintyre E, Verhoeyen E, Tesio M. Baboon envelope pseudotyped lentiviral vectors: a highly efficient new tool to genetically manipulate T-cell acute lymphoblastic leukaemia-initiating cells. Leukemia. 2017 Jan 13. doi: 10.1038/leu.2016.372. [Epub ahead of print] No abstract available.
  • Sarkozy C, Kaltenbach S, Faurie P, Canioni D, Berger F, Traverse-Glehen A, Ghesquieres H, Salles G, Bachy E, Alyanakian MA, Hermine O, Neven B, Macintyre E, Romana S, Molina TJ, Suarez F, Asnafi V, Bruneau J. Array-CGH predicts prognosis in plasma cell post-transplantation lymphoproliferative disorders. Genes Chromosomes Cancer. 2017 Mar;56(3):221-230.
  • 2016

  • Desjonquères A, Chevallier P, Thomas X, Huguet F, Leguay T, M, Bay JO, Tavernier E, Charbonnier A, Isnard F, Hunault M, Turlure P, Renaud M, Bastié JN, Himberlin C, Lepretre S, Lioure B, Lhéritier V, Asnafi V, Beldjord K, Lafage-Pochitaloff M, Béné MC, Ifrah N, Dombret H. Acute lymphoblastic leukemia relapsing after first-line pediatric-inspired therapy: a retrospective GRAALL study. Blood Cancer J. 2016 Dec 9;6(12):e504. doi: 10.1038/bcj.2016.111.
  • Manchev VT, Bouzid H, Antony-Debré I, Leite B, Meurice G, Droin N, Prebet T, Costello RT, Vainchenker W, Plo I, Diop M, Macintyre E, Asnafi V, Favier R, Baccini V, Raslova H. Acquired TET2 mutation in one patient with familial platelet disorder with predisposition to AML led to the development of pre-leukaemic clone resulting in T2-ALL and AML-M0. J Cell Mol Med. 2016 Dec 20. doi: 10.1111/jcmm.13051. [Epub ahead of print]
  • Ribeiro ST, Tesio M, Ribot JC, Macintyre E, Barata JT, Silva-Santos B. Casein kinase 2 controls the survival of normal thymic and leukemic γδ T cells via promotion of AKT signaling. Leukemia. 2016 Dec 16. doi: 10.1038/leu.2016.363. [Epub ahead of print]
  • Ceroi A, Masson D, Roggy A, Roumier C, Chagué C, Gauthier T, Philippe L, Lamarthée B, Angelot-Delettre F, Bonnefoy F, Perruche S, Biichle S, Preudhomme C, Macintyre E, Lagrost L, Garnache-Ottou F, Saas P. LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis. Blood. 2016 Dec 8;128(23):2694-2707.
  • Marçais A, Waast L, Bruneau J, Hanssens K, Asnafi V, Gaulard P, Suarez F, Dubreuil P, Gessain A, Hermine O, Pique C. Adult T cell leukemia aggressivenness correlates with loss of both 5-hydroxymethylcytosine and TET2 expression. Oncotarget. 2016 Nov 26. doi: 10.18632/oncotarget.13665. [Epub ahead of print]
  • Stunnenberg HG; International Human Epigenome Consortium., Hirst M. The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery. Cell. 2016 Nov 17;167(5):1145-1149.
  • Malcolm TI, Hodson DJ, Macintyre EA, Turner SD. Challenging perspectives on the cellular origins of lymphoma. Open Biol. 2016 Sep;6(9). pii: 160232.
  • Ettersperger J, Montcuquet N, Malamut G, Guegan N, Lopez-Lastra S, Gayraud S, Reimann C, Vidal E, Cagnard N, Villarese P, Andre-Schmutz I, Gomes Domingues R, Godinho-Silva C, Veiga-Fernandes H, Lhermitte L, Asnafi V, Macintyre E, Cellier C, Beldjord K, Di Santo JP, Cerf-Bensussan N, Meresse B. Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease. Immunity. 2016 Sep 20;45(3):610-25.
  • Bond J, Domaschenz R, Roman-Trufero M, Sabbattini P, Ferreiros-Vidal I, Gerrard G, Asnafi V, Macintyre E, Merkenschlager M, Dillon N. Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia. Oncotarget. 2016 Oct 4;7(40):65923-65936. doi: 10.18632/oncotarget.11688.
  • Trinquand A, Dos Santos NR, Tran Quang C, Rocchetti F, Zaniboni B, Belhocine M, Da Costa de Jesus C, Lhermitte L, Tesio M, Dussiot M, Cosset FL, Verhoeyen E, Pflumio F, Ifrah N, Dombret H, Spicuglia S, Chatenoud L, Gross DA, Hermine O, Macintyre E, Ghysdael J, Asnafi V. Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia. Cancer Discov. 2016 Sep;6(9):972-85. doi: 10.1158/2159-8290.CD-15-0675.
  • Emadali A, Hoghoughi N, Duley S, Hajmirza A, Verhoeyen E, Cosset FL, Bertrand P, Roumier C, Roggy A, Suchaud-Martin C, Chauvet M, Bertrand S, Hamaidia S, Rousseaux S, Josserand V, Charles J, Templier I, Maeda T, Bruder-Costa J, Chaperot L, Plumas J, Jacob MC, Bonnefoix T, Park S, Gressin R, Tensen CP, Mecucci C, Macintyre E, Leroux D, Brambilla E, Nguyen-Khac F, Luquet I, Penther D, Bastard C, Jardin F, Lefebvre C, Garnache F, Callanan MB. Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms. Blood. 2016 Jun 16;127(24):3040-53.
  • Bond J, Marchand T, Touzart A, Cieslak A, Trinquand A, Sutton L, Radford-Weiss I, Lhermitte L, Spicuglia S, Dombret H, Macintyre E, Ifrah N, Hamel JF, Asnafi V. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. Haematologica. 2016 Jun;101(6):732-40.
  • Malcolm TI, Villarese P, Fairbairn CJ, Lamant L, Trinquand A, Hook CE, Burke GA, Brugières L, Hughes K, Payet D, Merkel O, Schiefer AI, Ashankyty I, Mian S, Wasik M, Turner M, Kenner L, Asnafi V, Macintyre E, Turner SD. Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress. Nat Commun. 2016 Jan 12;7:10087. doi: 10.1038/ncomms10087.
  • Lepretre S, Touzart A, Vermeulin T, Picquenot JM, Tanguy-Schmidt A, Salles G, Lamy T, Béné MC, Raffoux E, Huguet F, Chevallier P, Bologna S, Bouabdallah R, Benichou J, Brière J, Moreau A, Tallon-Simon V, Seris S, Graux C, Asnafi V, Ifrah N, Macintyre E, Dombret H. Pediatric-Like Acute Lymphoblastic Leukemia Therapy in Adults With Lymphoblastic Lymphoma: The GRAALL-LYSA LL03 Study. J Clin Oncol. 2016 Feb 20;34(6):572-80. doi: 10.1200/JCO.2015.61.5385.
  • Tesio M, Trinquand A, Macintyre E, Asnafi V. Oncogenic PTEN functions and models in T-cell malignancies. Oncogene. 2016 Jul 28;35(30):3887-96. doi: 10.1038/onc.2015.462. Review.
  • Bond J, Touzart A, Cieslak A, Trinquand A, Marchand T, Escoffre M, Contet A, Muller M, Schmitt C, Fest T, Asnafi V, Macintyre E. NAP1L1-MLLT10 is a rare recurrent translocation that is associated with HOXA activation and poor treatment response in T-cell acute lymphoblastic leukaemia. Br J Haematol. 2016 Aug;174(3):470-3. doi: 10.1111/bjh.13772. No abstract available.
  • Bachy E, Urb M, Chandra S, Robinot R, Bricard G, de Bernard S, Traverse-Glehen A, Gazzo S, Blond O, Khurana A, Baseggio L, Heavican T, Ffrench M, Crispatzu G, Mondière P, Schrader A, Taillardet M, Thaunat O, Martin N, Dalle S, Le Garff-Tavernier M, Salles G, Lachuer J, Hermine O, Asnafi V, Roussel M, Lamy T, Herling M, Iqbal J, Buffat L, Marche PN, Gaulard P, Kronenberg M, Defrance T, Genestier L. CD1d-restricted peripheral T cell lymphoma in mice and humans. J Exp Med. 2016 May 2;213(5):841-57.
  • Lepretre S, Touzart A, Vermeulin T, Picquenot JM, Tanguy-Schmidt A, Salles G, Lamy T, Béné MC, Raffoux E, Huguet F, Chevallier P, Bologna S, Bouabdallah R, Benichou J, Brière J, Moreau A, Tallon-Simon V, Seris S, Graux C, Asnafi V, Ifrah N, Macintyre E, Dombret H. Pediatric-Like Acute Lymphoblastic Leukemia Therapy in Adults With Lymphoblastic Lymphoma: The GRAALL-LYSA LL03 Study. J Clin Oncol. 2016 Feb 20;34(6):572-80.
  • 2015

  • Minard-Colin V, Brugières L, Reiter A, Cairo MS, Gross TG, Woessmann W, Burkhardt B, Sandlund JT, Williams D, Pillon M, Horibe K, Auperin A, Le Deley MC, Zimmerman M, Perkins SL, Raphael M, Lamant L, Klapper W, Mussolin L, Poirel HA, Macintyre E, Damm-Welk C, Rosolen A, Patte C. Non-Hodgkin Lymphoma in Children and Adolescents: Progress Through Effective Collaboration, Current Knowledge, and Challenges Ahead. J Clin Oncol. 2015 Sep 20;33(27):2963-74.
  • Dussiau C, Trinquand A, Lhermitte L, Latiri M, Simonin M, Cieslak A, Bedjaoui N, Villarèse P, Verhoeyen E, Dombret H, Ifrah N, Macintyre E, Asnafi V. Targeting IRAK1 in T-cell acute lymphoblastic leukemia. Oncotarget. 2015 Aug 7;6(22):18956-65.
  • Delfau-Larue MH, Klapper W, Berger F, Jardin F, Briere J, Salles G, Casasnovas O, Feugier P, Haioun C, Ribrag V, Thieblemont C, Unterhalt M, Dreyling M, Macintyre E, Pott C, Hermine O, Hoster E; European Mantle Cell Lymphoma Network. High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood. 2015 Jul 30;126(5):604-11.
  • Tesio M, Tang Y, Müdder K, Saini M, von Paleske L, Macintyre E, Pasparakis M, Waisman A, Trumpp A. Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway. J Exp Med. 2015 Apr 6;212(4):525-38.
  • Navarro JM, Touzart A, Pradel LC, Loosveld M, Koubi M, Fenouil R, Le Noir S, Maqbool MA, Morgado E, Gregoire C, Jaeger S, Mamessier E, Pignon C, Hacein-Bey-Abina S, Malissen B, Gut M, Gut IG, Dombret H, Macintyre EA, Howe SJ, Gaspar HB, Thrasher AJ, Ifrah N, Payet-Bornet D, Duprez E, Andrau JC, Asnafi V, Nadel B. Site- and allele-specific polycomb dysregulation in T-cell leukaemia. Nat Commun. 2015 Jan 23;6:6094.
  • Dhédin N, Huynh A, Maury S, Tabrizi R, Beldjord K, Asnafi V, Thomas X, Chevallier P, Nguyen S, Coiteux V, Bourhis JH, Hichri Y, Escoffre-Barbe M, Reman O, Graux C, Chalandon Y, Blaise D, Schanz U, Lhéritier V, Cahn JY, Dombret H, Ifrah N; GRAALL group. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood. 2015 Apr 16;125(16):2486-96.
  • Barete S, Lortholary O, Damaj G, Hirsch I, Chandesris MO, Elie C, Hamidou M, Durieu I, Suarez F, Grosbois B, Limal N, Gyan E, Larroche C, Guillet G, Kahn JE, Casassus P, Amazzough K, Coignard-Biehler H, Georgin-Lavialle S, Lhermitte L ,Fraitag S, Canioni D, Dubreuil P, Hermine O. Long-term efficacy and safety ofcladribine (2-CdA) in adult patients with mastocytosis. Blood. 2015 May 22. pii: blood-2014-12-614743. [Epub ahead of print] PubMed PMID: 26002962.
  • Kalina T, Flores-Montero J, Lecrevisse Q, Pedreira CE, van der Velden VH, Novakova M, Mejstrikova E, Hrusak O, Böttcher S, Karsch D, Sędek Ł, Trinquand A, Boeckx N, Caetano J, Asnafi V, Lucio P, Lima M, Helena Santos A, Bonaccorso P, van der Sluijs-Gelling AJ, Langerak AW, Martin-Ayuso M, Szczepański T, van Dongen JJ, Orfao A. Quality assessment program for EuroFlow protocols: summary results of four-year (2010-2013) quality assurance rounds. Cytometry A. 2015 Feb;87(2):145-56.
  • Tesio M, Trinquand A, Macintyre E, Asnafi V. Oncogenic PTEN functions and models in T-cell malignancies. Oncogene. 2015 Nov 30. doi: 10.1038/onc.2015.462. [Epub ahead of print] Review.
  • Chercheur statutaire
    Vahid Asnafi
    Chercheur hospitalo-Universitaire
    +33 (0)1 44 49 49 14
    Chantal Brouzes
    Clinicien(ne)
    +33 (0)1 44 49 49 32
    Ludovic Lhermitte
    Enseignant Chercheur
    +33 (0)1 44 49 49 33
    Elizabeth Macintyre
    Chercheur hospitalo-Universitaire
    +33 (0)1 44 49 49 47
    Ambroise Marcais
    Chercheur hospitalo-Universitaire
    David Sibon
    Chercheur hospitalo-Universitaire
    Melania Tesio
    Chargé(e) de Recherche classe Normale
    +33(0)1 44 49 40 98
    Chercheur non statutaire
    Eugénie Duroyon
    Assistant hospitalier universitaire
    Thomas Steimle
    Assistant spécialiste
    ITA statutaire
    Patrick Villarese
    Ingénieur
    +33 (0)1 44 49 49 41
    ITA non statutaire
    Nicolas Gaidot
    Ingénieur(e) en expérimentation animale
    Guillaume Hypolite
    Ingénieur
    Aurélie Le Nezet
    -
    Post-doctorant
    Guillaume Andrieu
    Post-doctorant(e)
    Agata Cieslak
    Technicien(ne) en biologie
    +33 (0)1 44 49 40 98
    Doctorant
    Emilie Dourthe
    Doctorant(e)
    Mathieu Simonin
    Doctorant(e)
    +33 (0)1 44 38 18 78
    Charlotte Smith
    Doctorant(e)
    Etudiant
    Marine Delecourt
    Master 2
    Josquin Moraly
    Etudiant
    Adresse

    Notice: Undefined variable: contact_addr in /homepages/40/d483507699/htdocs/location.php on line 25
    Parrain(s)
    S.A.R. la Princesse Caroline de Hanovre qui, à travers la Fondation Princesse Grace, soutient déjà la recherche medicale et tout ce qui contribue à soulager les enfants malades en France et dans le monde, a accepté de s'engager à nos cotés pour que ce centre de medecine moleculaire, tourné entre autres vers les pathologies des enfants, prenne de vitesse les maladies et continue à relever les defis actuels.

    Notice: Undefined index: screen_height in /homepages/40/d483507699/htdocs/index.php on line 344