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 : 18 )
- 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 -
- 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 )
- 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 - Histological characterization of liver involvement in systemic mastocytosis.
Julien Rossignol , Danielle Canioni , Achille Aouba , Cristina Bulai-Livideanu , St¨¦phane Barete , Charles Lancesseur , Laura Polivka , Marine Madrange , Thomas Ballul , Antoine Neuraz , Celine Greco , Julie Agopian , Fabienne Brenet , Patrice Dubreuil , Richard Lemal , Olivier Tournilhac , Louis Terriou , David Launay , Laurence Bouillet , Cl¨¦ment Gourguechon - Effective Anti¨CSARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders
Julien Rossignol , Amani Ouedrani , Cristina Bulai Livideanu , St¨¦phane Barete , Louis Terriou , David Launay , Richard Lemal , Celine Greco , Laurent Frenzel , Cecile Meni , Christine Bodemere-Skandalis , Laura Polivka , Anne-Florence Collange , Hassiba Hachichi , Sonia Bouzourine , Djazira Nait Messaoud , Mathilde Negretto , Laurence Vendrame , Marguerite Jambou , Marie Gousseff - No Detectable Alteration of Inorganic Allogeneic Bone Matrix Colonizing Mesenchymal Cells: A Step Towards Personalized Bone Grafts
Roger Erivan , Nicolas Samper , Guillaume Villatte , St¨¦phane Boisgard , St¨¦phane Descamps , Marc Berger - Management of Immunosuppression After Kidney Transplant Failure: Effect on Patient Sensitization
Marine Freist , Dominique Bertrand , Elodie Bailly , C¨¦line Lambert , Paul Olivier Rouzaire , Richard Lemal , Julien Aniort , Matthias B¨¹chler , Anne Elisabeth Heng , Cyril Garrouste - Validation of response assessment according to international consortium for MDS/MPN criteria in chronic myelomonocytic leukemia treated with hypomethylating agents
M Duchmann , B Braun , J.B. Micol , P Platzbecker , P. Park , P Pilorge , R Beyne-Rauzy , N. Vey , M S¨¦bert , B. Gruson , P. Dumas , R Guieze , M.-L. Chretien , L Laribi , C Chait , L. Legros , L Sahnes , P Hirsch , C. Salanoubat , E. Solary - Optical genome mapping for prenatal diagnosis: A prospective study
Carole Goumy , Zangb¨¦wend¨¦ Guy Ouedraogo , Gwendoline Soler , Eleonore Eymard-Pierre , H¨¦l¨¨ne Laurichesse , Am¨¦lie Delabaere , Denis Gallot , Pamela Bouchet , Isabelle Perthus , C¨¦line Pebrel-Richard , Laetitia Gouas , Ga?lle Salaun , J¨¦r?me Salse , Lauren V¨¦ron¨¨se , Andrei Tchirkov - Gilteritinib activity in refractory or relapsed FLT3-mutated acute myeloid leukemia patients previously treated by intensive chemotherapy and midostaurin: a study from the French AML Intergroup ALFA/FILO
Pierre-Yves Dumas , Emmanuel Raffoux , Emilie B¨¦rard , Sarah Bertoli , Marie-Anne Hospital , Ma?l Heiblig , Yohann Desbrosses , Caroline Bonmati , C¨¦cile Pautas , Juliette Lambert , Corentin Orvain , Anne Banos , Florence Pasquier , Pierre Peterlin , Tony Marchand , Madalina Uzunov , Jamil¨¦ Frayfer , Pascal Turlure , Thomas Cluzeau , Eric Jourdan - Semaphorin 7A: A novel marker of disease activity in Gaucher disease
M¨¦lanie Franco , Nelly Reihani , Lucie Dupuis , Emmanuel Collec , Thierry Billette de Villemeur , Marine de Person , Fathi Moussa , Marc Berger , Nadia Belmatoug , Caroline Le van Kim - ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome
Erin Parry , Camilla Lemvigh , Stephanie Deng , Nathan Dangle , Neil Ruthen , Binyamin Knisbacher , Julien Bros¨¦us , S¨¦bastien Hergalant , Romain Gui¨¨ze , Shuqiang Li , Wandi Zhang , Connor Johnson , Jaclyn Long , Shanye Yin , Lillian Werner , Annabelle Anandappa , Noelia Purroy , Satyen Gohil , Giacomo Oliveira , Pavan Bachireddy
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