UMR 1131 – Equipe 1 - Cellules souches et microenvironnement
Présentation
It is generally accepted that myelodysplastic syndromes (MDS) originates as a result of a multistep process of leukemogenesis, implicating genetic, epigenetic and immune-mediated alterations of an early hematopoietic stem cell (HSC). However, alterations in the BM microenvironment may also have a role in MDS pathogenesis. The possible involvement of the BM mesenchymal stem cells (MSC) in the pathogenetic/pathophysiologic process of MDS has been recently identified using mouse models (Raaijmakers MH et al. Nature 2010, Walkley CR et al. Cell 2007) but existing data on MSCs' cytogenetic and functional integrity in MDS patient samples are more controversial. As no conclusive data on the characteristics of BM MSCs in MDS have been reported so far, future studies should aim at elucidating whether they belong primarily to the abnormal clone or whether they are indirectly damaged. Analysis of the cross talk between MSC and HSC from MDS should also need to be investigated.
Thèmes de recherche
Our specific aims are:
To develop a robust in vivo model which recapitulates the natural history of MDS using the NOD/SCID-Il2 gamma c null (NSG) and NSG-GMS3 mice and potentially correlate the engraftment with clinical outcome and/or molecular classification of MDS.
To identify and calculate the frequency of the MDS initiating cells (MDS-IC) using FACS sorting strategies and limiting dilution analysis.
To analyse the genetic variegation of the HSC/progenitor compartment in MDS and investigate the clonal variegation of HSC before and after transplantation
To evaluate the genetic, epigenetic and functional status of the MSC compartment from MDS patients.
To evaluate the effect of MDS cells on the stroma microenvironment /stem cell niche as well as the effect of MSC from MDS patients on normal human HSC both in vitro and in vivo.
Equipes de recherche
The project is coordinated by Christine DOSQUET together with Dominique BONNET who is a senior group leader, Haematopoietic Stem cell Laboratory (Francis Crick Institute, UK). A PhD student Marie GOULARD and a master student, Freddy CROZILHAC work on this project
Publications
KILADJIAN JJ, CHEVRET S, DOSQUET C, CHOMIENNE C, RAIN JD. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol, 2011 Oct 10; 29 (29):3907-13.
Moreau M, Mourah S, Dosquet C.beta-Catenin and NF-kappa B cooperate to regulate the uPA/uPAR system in cancer cells. Int J Cancer, 2011 Mar 15; 128 (6):1280-92.
RIVET J, MOURAH S, MURATA H, MOUNIER N, PISONERO H, MONGIAT-ARTUS P, TEILLAC P, CALVO F, JANIN A, DOSQUET C. VEGF and VEGFR-1 are coexpressed by epithelial and stromal cells of renal cell carcinoma. Cancer, 2008 Jan 15; 112(2):433-42.
KELLOUCHE S, MARTIN C, KORB G, REZZONICO R, BOUARD D, BENBUNAN M, DUBERTRET L, SOLER C, LEGRAND C, DOSQUET C. Tissue engineering for full-thickness burns: a dermal substitute from bench to bedside. Biochem Biophys Res Commun, 2007 Nov 23; 363(3):472-8.
KELLOUCHE S, MOURAH S, BONNEFOY A, SCHOEVAERT D, PODGORNIAK MP, CALVO F, HOYLAERTS MF, LEGRAND C, DOSQUET C. Platelets, thrombospondin-1 and human dermal fibroblasts cooperate for stimulation of endothelial cell tubulogenesis through VEGF and PAI-1 regulation. Exp Cell Res, 2007 Feb 1; 313(3):486-99.
Autres contacts
Chef D’équipe :
Dr. Christine DOSQUET MD, PhD
University Paris-Diderot (Paris-Sorbonne-Cité)
INSERM UMR-S1131 – Institut Universitaire d’Hématologie
Hôpital Saint-Louis (AP-HP)
Tél. : +33 1 42 49 95 65
FAX : +33 1 42 38 54 76
Email: christine.dosquet@aphp.fr
