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 : 20 )
- BAY Jacques Olivier -
- BERGER Marc -
- GUIEZE Romain -
- ROUZAIRE Paul -
- TCHIRKOV Andrei -
- TOURNILHAC Olivier -
- VERONESE Lauren -
- BOURGNE Celine -
- GARCIA Manon -
- MOINARD Sylvain -
- 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 )
- Flower shaped nuclei and blue©\green inclusions in heatstroke
Emeline Tourret , Jo¨¦vin Besombes - Comparison of umbilical cord blood allogeneic stem cell transplantation vs. auto©\ SCT for adult acute myeloid leukemia patients in second complete remission at transplant: a retrospective study on behalf of the SFGM ©\ TC
Patrice Chevallier , Myriam Labopin , Gerard Socie , Marie-There Rubio , Didier Blaise , Stephane Vigouroux , Anne Huynh , Mauricette Michallet , Jacques-Olivier Bay , S¨¦bastien Maury , Ibrahim Yakoub-Agha , Nathalie Fegueux , Eric Deconinck , Nathalie Contentin , Natacha Maillard , Claude-Eric Bulabois , Sylvie Francois , Reman Oumedaly , Nicole Raus , Mohamad Mohty - Faster clinical decisions in B©\cell acute lymphoblastic leukaemia: A single flow cytometric 12©\colour tube improves diagnosis and minimal residual disease follow©\up
Benjamin Lebecque , Joevin Besombes , Louis©\thomas Dannus , Marie de Antonio , Victoria Cacheux , Victoria Gr¨¨ze , Valentin Montagnon , Lauren Veronese , Andrei Tchirkov , Olivier Tournilhac , Marc Berger , Richard Veyrat-Masson - Pyoderma gangrenosum-like neutrophilic dermatosis as an adverse effect of menin-KMT2A inhibitor therapy for acute myeloid leukaemia
Urbain Tauveron-Jalenques , Khadim Sarr , Romain Gui¨¨ze , Chlo¨¦ Giordano , Jacques Rouanet , Sandrine Hayette , Carole Chevenet , Ma?l Heiblig , Aur¨¦lie Ravinet - Droplet digital PCR allows vector copy number assessment and monitoring of experimental CAR T cells in murine xenograft models or approved CD19 CAR T cell-treated patients
Rafik Haderbache , Walid Warda , Eric Hervouet , Mathieu Neto da Rocha , Rim Trad , Vincent Allain , Clementine Nicod , Catherine Thieblemeont , Nicolas Boissel , Pauline Varlet , Ibrahim Yakoub Agha , Lucie Bouquet , Melanie Guiot , Fabienne Venet , Pierre Sujobert , Xavier Roussel , Paul-Oliver Rouzaire , Denis Caillot , Olivier Casasnovas , Jean Christophe Bories - Management and prognosis of malignant peripheral nerve sheath tumors: The experience of the French Sarcoma Group (GSF-GETO)
Thibaud Valentin , A. Le Cesne , Isabelle Ray-Coquard , A. Italiano , G. Decanter , Emmanuelle Bompas , Nicolas Isambert , J. Thariat , Claude Linassier , F. Bertucci , J.O. Bay , A. Bellesoeur , Nicolas Penel , S. Le Guellec , T. Filleron , C. Chevreau - Development of a disease-specific graded prognostic assessment index for the management of sarcoma patients with brain metastases (Sarcoma-GPA)
Anna Patrikidou , Lo?c Chaigneau , Nicolas Isambert , Kyriaki Kitikidou , Ryan Shanley , Isabelle Ray-Coquard , Thibaud Valentin , Bettina Malivoir , Maryline Laigre , Jacques-Olivier Bay , Laurence Moureau-Zabotto , Emmanuelle Bompas , Sophie Piperno-Neumann , Nicolas Penel , Thierry Alcindor , C¨¦cile Guillemet , Florence Duffaud , Anne H¨¹gli , C¨¦cile Le P¨¦choux , Fr¨¦d¨¦ric Dhermain - Devenir obst¨¦trical des patientes transplant¨¦es r¨¦nales suivies dans une maternit¨¦ de type III. ?tude r¨¦trospective de 2000 ¨¤ 2020
Aur¨¦lie Reitz , Marion Rouzaire , Romain Cahierc , Bruno Pereira , Richard Lemal , Cyril Garrouste , Denis Gallot - Severe Colchicine Intoxication in a Renal Transplant Recipient on Cyclosporine
Cyril Garrouste , C Philipponnet , S Kaysi , I Enache , A Tiple , A E Heng - Harmful effect of saline infusion in a patient with glycyrrhizic acid poisoning
Natacha Caubet-Kamar , Marie Tubery , Cyril Garrouste , Dominique Lauque , Nassim Kamar
Production scientifique depuis 2021
- Expression contr?l¨¦e d'un g¨¨ne th¨¦rapeutique dans les lymphocytes T humains pour utilisation en immunoth¨¦rapie cellulaire - 2022