Role of intra-Clonal HEterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias
UR 7453 / UCA
- Adresse :
- CHU Estaing
H¨¦matologie Biologique
1, Place Lucie et Raymond Aubrac
63003 CLERMONT-PT招财进宝
- T¨¦l :
- 04-73-750-682
- Sur Internet :
- 193.49.117.47/weblabs/web/app_chelter.php/
Responsables
- Directeur de laboratoire
- Marc BERGER
- Directeur Adjoint
- Olivier TOURNILHAC
Composition ¨¦quipe ( effectif total : 19 )
- BAY Jacques Olivier -
- BERGER Marc -
- GUIEZE Romain -
- ROUZAIRE Paul -
- TCHIRKOV Andrei -
- TOURNILHAC Olivier -
- VERONESE Lauren -
- BOURGNE Celine -
- GARCIA Manon -
- BESOMBES Joevin -
- CROIZIER Carolyne -
- GARROUSTE Cyril -
- BESOMBES Joevin -
- CROIZIER Carolyne -
- GARROUSTE Cyril -
- LEBECQUE Benjamin -
- SAUGUES Sandrine -
- TASSIN Thomas -
- TRIBALAT Nathalie -
Th¨¨mes de Recherche
Version Fran?aise English version?L¡¯apport des th¨¦rapies cibl¨¦es a ¨¦t¨¦ consid¨¦rable, en particulier les inhibiteurs de prot¨¦ines ¨¤ activit¨¦ tyrosine kinase. Leur utilisation a notamment boulevers¨¦ la prise en charge des h¨¦mopathies chroniques mais dans la plupart des cas, une sous-population de cellules r¨¦siste in vivo au traitement et est responsable de la persistance de la maladie ou de sa r¨¦surgence au cours du traitement ou ¨¤ l¡¯arr¨ºt th¨¦rapeutique.
Notre ¨¦quipe s¡¯int¨¦resse ¨¤ 2 aspects de cette r¨¦sistance : 1) L¡¯h¨¦t¨¦rog¨¦n¨¦it¨¦ intra-clonale et son ¨¦volution au cours du temps et 2) La relation du clone tumoral avec le tissu environnant. Nous nous int¨¦ressons ¨¤ trois entit¨¦s clairement d¨¦finies sur le plan nosologique, d¡¯¨¦volution chronique et dans lesquelles le d¨¦veloppement de th¨¦rapeutiques cibl¨¦es est d¨¦sormais un ¨¦l¨¦ment fondamental constituant m¨ºme parfois l¡¯unique traitement. Il s¡¯agit d¡¯une part de la Leuc¨¦mie My¨¦lo?de Chronique (LMC), issue de la lign¨¦e my¨¦lo?de, d¡¯autre part de la Leuc¨¦mie Lympho?de Chronique (LLC) et de la macroglobulin¨¦mie de Waldenstr?m (MW) issues de la lign¨¦e lympho?de de ph¨¦notype B.
Notre strat¨¦gie comprend une ¨¦tude des m¨¦canismes intrins¨¨ques par :
- une approche ¨¦pig¨¦n¨¦tique de l¡¯h¨¦t¨¦rog¨¦n¨¦it¨¦ intra-clonale dans le mod¨¨le de la Leuc¨¦mie My¨¦loide Chronique, en recherchant des m¨¦canismes de survie/r¨¦sistance aux inhibiteurs de tyrosine kinase ind¨¦pendants de l¡¯activit¨¦ TK de la prot¨¦ine BCR-ABL (manuscrit en pr¨¦paration)
- une analyse du profil de mutations g¨¦niques par NGS dans la Leuc¨¦mie Lympho?de Chronique qui a permis de mieux comprendre l¡¯h¨¦t¨¦rog¨¦n¨¦it¨¦ intra-clonale ; un travail compl¨¦mentaire par ¨¦tude longitudinale est en cours.
Cette strat¨¦gie est compl¨¦t¨¦e par une approche extrins¨¨que par une ¨¦tude du microenvironnement leuc¨¦mique au plus pr¨¨s des conditions in vivo en nous int¨¦ressant ¨¤ l¡¯environnement naturel de la maladie. Nous nous int¨¦ressons dans ce contexte au tissu m¨¦dullaire.
Les deux aspects du projet permettront d¡¯identifier des sous-populations cibles du clone leuc¨¦mique, de mieux comprendre leurs interactions avec le microenvironnement et leur r?le dans la r¨¦sistance aux th¨¦rapies cibl¨¦es afin d¡¯¨¦laborer des strat¨¦gies th¨¦rapeutiques compl¨¦mentaires.?
"The contribution of targeted therapies has been considerable, especially inhibitors of tyrosine kinase activity. In particular, their use has upset the management of chronic hemopathies, but in most cases a subpopulation of cells that resists in vivo treatment and is responsible for the persistence of the disease or its relapse during treatment or after stopping treatment.
Our team is interested in 2 aspects of this resistance: 1) The intraclonal heterogeneity and its evolution and 2) The relationship between the tumor clone and the surrounding tissue. We are interested in three entities that are clearly defined nosologically, of chronic evolution and in which the development of targeted therapies is now a fundamental element and even sometimes the only treatment. Chronic myeloid leukemia (CML), from myeloid lineage, and Chronic Lymphoid Leukemia (CLL) and Waldenstr?m macroglobulinemia (MW) from the B cell lymphoid lineage.
Our strategy includes a study of intrinsic mechanisms by:
- an epigenetic approach to study the intraclonal heterogeneity in the Chronic Myeloid Leukemia model, by looking for mechanisms of survival/resistance to tyrosine kinase inhibitors, independent of the TK activity of the BCR-ABL protein (manuscript in preparation)
- an analysis of the profile of NGS gene mutations in Chronic Lymphocytic Leukemia, which allowed a better understanding of intra-clonal heterogeneity; Complementary work by longitudinal study is under way.
This strategy is complemented by an extrinsic approach by studying the leukemic microenvironment as close as possible to the in vivo conditions by focusing on the natural environment of the disease. In this context, we are interested in bone marrow tissue, in particular its tissue subunits called hematons.
Both aspects of the project will identify target subpopulations of the leukemic clone, to better understand and their role in resistance to targeted therapies and their interactions with the microenvironment in order to develop complementary therapeutic strategies."
Publications ( HAL )
- Temporal regulation of transgene expression controlled by amino acid availability in human T cells
Aurore Doug¨¦ , Alain Bruhat , Paul Rouzaire - NUTRIREG-T cells: a nutrition-based regulatory system of transgene expression in human T cells
Aurore Doug¨¦ , Alain Bruhat , Paul Rouzaire - Long-Term Follow-Up of the Prospective Randomized AATT Study (Autologous or Allogeneic Transplantation in Patients With Peripheral T-Cell Lymphoma)
Olivier Tournilhac , Bettina Altmann , Birte Friedrichs , Kamal Bouabdallah , Mathieu Leclerc , Guillaume Cartron , Pascal Turlure , Peter Reimer , Eva Wagner-Drouet , Laurence Sanhes , Roch Houot , Murielle Roussel , Frank Kroschinsky , Peter Dreger , Andreas Viardot , Laurence de Leval , Andreas Rosenwald , Philippe Gaulard , Gerald. Wulf , Alban Villate - Identification of primary mediastinal B-cell lymphomas with higher clonal dominance and poorer outcome using 5' RACE
Vincent Camus , Mathieu Viennot , Pierre-Julien Viailly , Fanny Drieux , Elena-Liana Veresezan , Victor Bob¨¦e , Vinciane Rainville , Elodie Bohers , Pierre Sesques , Corinne Haioun , Eric Durot , Michael Bayaram , C¨¦dric Rossi , Laurent Martin , Dominique Penther , Sophie Kaltenbach , Julie Bruneau , J¨¦r?me Paillassa , Olivier Tournilhac , Nicolas Gower - Anomalies cytog¨¦nomiques et dysfonction t¨¦lom¨¦rique des leuc¨¦mies chroniques et tumeurs solides
L Veronese - Feasibility of Optical Genome Mapping from Placental and Umbilical Cord Sampled after Spontaneous or Therapeutic Pregnancy Termination
Carole Goumy , Zangb¨¦wend¨¦ Guy Ouedraogo , Elodie Bellemonte , Eleonore Eymard-Pierre , Gwendoline Soler , Isabelle Perthus , C¨¦line Pebrel-Richard , Laetitia Gouas , Ga?lle Salaun , Lauren V¨¦ron¨¨se , H¨¦l¨¨ne Laurichesse , Claude Darcha , Andrei Tchirkov - Optical Genome Mapping in Routine Cytogenetic Diagnosis of Acute Leukemia
Gwendoline Soler , Zangb¨¦wend¨¦ Guy Ouedraogo , Carole Goumy , Benjamin Lebecque , Gaspar Aspas Requena , Aur¨¦lie Ravinet , Justyna Kanold , Lauren V¨¦ron¨¨se , Andrei Tchirkov - Blinatumomab after R-CHOP bridging therapy for patients with Richter transformation: a phase 2 multicentre trial
Romain Gui¨¨ze , Lo?c Ysebaert , Damien Roos-Weil , Luc-Mathieu Fornecker , Emmanuelle Ferrant , Lysiane Molina , Th¨¦r¨¨se Aurran , Aline Clavert , Sophie de Guibert , Anne-Sophie Michallet , Alain Saad , Bernard Dr¨¦nou , Philippe Quittet , B¨¦n¨¦dicte Hivert , Kamel Laribi , Julie Gay , Anne Quinquenel , Julien Broseus , Val¨¦rie Rouille , David Schwartz - Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome
Erin Parry , Ignaty Leshchiner , Romain Gui¨¨ze , Connor Johnson , Eugen Tausch , Sameer Parikh , Camilla Lemvigh , Julien Bros¨¦us , S¨¦bastien Hergalant , Conor Messer , Filippo Utro , Chaya Levovitz , Kahn Rhrissorrakrai , Liang Li , Daniel Rosebrock , Shanye Yin , Stephanie Deng , Kara Slowik , Raquel Jacobs , Teddy Huang - Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.
Josquin Moraly , Julien Rossignol , Claire Rouzaud , Thomas Gabas , Hassiba Bouktit , Ludovic Lhermitte , Danielle Canioni , Sylvie Fraitag , Julie Bruneau , Stephane Barete , Felipe Suarez , Thomas Ballul , C¨¦cile Meni , Laura Polivka , Louis Terriou , David Launay , Laurence Bouillet , Caroline Gaudy-Marqueste , Marie Gousseff , Edwige Le Mouel
Production scientifique depuis 2020
- Expression contr?l¨¦e d'un g¨¨ne th¨¦rapeutique dans les lymphocytes T humains pour utilisation en immunoth¨¦rapie cellulaire - 2022