Acute Leukemia – GEO Team
IGDR UMR 6290 CNRS, Rennes
– Marie-Dominique GALIBERT (Professeur des Universités & Praticien hospitalier UR1-CHU)
– Lise BOUSSEMART (Maître de conférences – Praticien hospitalier UR1-CHU)
– Sébastien CORRE (Chargé de recherche INSERM)
– Virginie GANDEMER (Professeur des Universités – Praticien hospitalier UR1-CHU)
– David GILOT (Maître de conférences UR1)
Thématique de recherche générale en oncopédiatrie
Chromosomal translocation involving transcription factors can result in cancer. The ETV6/RUNX1 acute lymphoblastic leukemia is the most represented hematological malignancy found in children and is related to the fusion of the two transcription factors: the repressor ETV6 and the activator or repressor RUNX1. We aim at deciphering the mechanisms implicated in the development of leukemic cells and understanding late relapses observed in ETV6/RUNX1 leukemic patients.
This will permit to establish a hierarchy of signaling programs required for leukemia development, from the onset to the relapse, and will allow us to propose targeted therapeutic targets.
Our research interest will focus on deciphering mechanisms of action of the key transcription factor RUNX1 involved in hematopoiesis and the leukemia-initiating transcription factor ETV6/RUNX1 commonly found in one fifth of pediatric leukemia.
More specifically, we will:
-characterize RUNX1-related transcription factor complexes by identifying the transcriptional partners of RUNX1 and ETV6/RUNX1,
-determine regulation activity of the complexes using histone-mark immunoprecipitation,
-define genome-wide the subset of genes directly modulated by those transcription factor complexes using chromatin immunoprecipitation followed by sequencing and global gene expression approaches,
-determine DNA binding motifs for those transcription factor complexes,
-explore the role of the transcriptonal complexes in hematopoieis using zebrafish hematopoieisis as a readout,
-define the role of the complexes in the onset and progression of leukemia using leukemic cells xenografts model in mouse,
-and ultimately propose those complexes as specific therapeutic target for ETV6/RUNX1 leukemia.
Our research interest will also focus on exploring molecular mechanisms responsible for relapses of leukemic patients. Previously, we demonstrated that the tetraspanin CD9 could interfere with CXCL12/CXCR4 signaling by enhancing RAC1 activation via its C-terminal sequence. We demonstrated that RAC1 activation enhanced actin rearrangement and the formation of cytoplasmic extensions, promoting chemotactic migration to towards CXCL12 in the testis, a recognized site of late relapses for leukemia.
-better characterize the interactions between RAC1 and CD9 and study their impact on cytoskeleton,
-explore specificities and tumorigenic abilities of the lymphoblasts that have disseminated in testis. To achieve this, we will perform serial xenografts in immunodeficient mice and analyze their phenotypic properties according to CD9 expression,
-understand the transcriptional regulation of CD9 by exploring two mechanisms: (1) the regulation of CD9 by miRNAs through an indirect and direct manner using CD9 RNA-immonuprecipitation and analysis of miRNA in patients blasts, and (2) the role of hypoxia mediated by HIF.
Teams of Hatem Sabaawy (Cancer Institute of New Jersey, USA), Jason Carroll (Cambridge, UK), Gilles Salbert UMR CNRS 6290, Rennes, France); Vincent Praloran (INSERM, Bordeaux, France)
Clinical French network for pediatric leukemia.
Corre S*, Tardif N*, Mouchet N, Leclair HM, Boussemart L, Gautron A, Bachelot L, Perrot A, Soshilov A, Rogiers A, Rambow F, Dumontet E, Tarte K, Bessede A, Guillemin GJ, Marine JC, Denison MS, Gilot D*, Galibert MD*. Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nat. Commun. 2018 Nov. – * Equal contribution
Debaize L*, Jakobczyk H*, Avner S, Gaudichon J, Rio AG, Sérandour AA, Dorsheimer L, Chalmel F, Carroll JS, Zörnig M, Rieger MA, Delalande O, Salbert G, Galibert MD, Gandemer V, Troadec MB. Interplay between transcription regulators RUNX1 and FUBP1 activates an enhancer of the oncogene c-KIT and amplifies cell proliferation. Nucleic Acids Res. 2018 Nov. – * Equal contribution
Gilot D*, Migault M*, Bachelot L, Journé F, Rogiers A, Donnou-Fournet E, Mogha A, Mouchet N, Pinel-Marie ML, Mari B, Montier T, Corre S, Gautron A, Rambow F, El Hajj P, Ben Jouira R, Tartare-Deckert S, Marine JC, Felden B, Ghanem G, Galibert MD. A non-coding funcion of TYRP1 mRNA promotes melanoma growth. Nat.Cell Biol. 2017 Nov. – * Equal contribution
Debaize L, Jakobczyk H, Rio AG, Gandemer V, Troadec MB.Optimization of proximity ligation assay (PLA) for detection of protein interactions and fusion proteins in non-adherent cells : application to pre-B lymphocytes. Mol. Cytogenet. 2017 Jul
Arnaud MP, Vallée A, Robert G, Bonneau J, Leroy C, Varin-Blank N, Rio AG, Troadec MB, Galibert MD and Gandemer V. CD9, a key actor in the dissemination of lymphoblastic leukemia, modulating CXCR4-mediated migration via RAC1 signaling. Blood. 2015 Oct.