CRCINA - INSERM UMR1232
Department "Nuclear Oncology and Hematological Malignancies Department (NOHMAD)"
Team 10: “ Regulation of Bcl2 and p53 networks in Multiple Myeloma and Mantle Cell Lymphoma ”
Multiple myeloma is an highly heterogeneous disease and the second most prevalent hematologic malignancy. Despite significant progress made during the last 10 years with the successful introduction of new chemotherapeutic regimens (based on the use of the proteasome inhibitors and Imids) MM remains incurable because patients develop multidrug-resistant disease.
Our team has established numerous human myeloma cell lines (HMCLs) and has recently demonstrated that our collection of more than 40 HMCLs is representative of the heterogeneity of patients. All HMCLs are characterized for their gene expression profile as well as for their response to myeloma growth factors (IL6, IGF1, SCF, EGF family) and sensitivity to current clinical drugs (melphalan, bortezomib, lenalidomide, dexamethasone). In vitro studies performed by our team with the HMCL’s panel allowed to identify biomarkers and therapeutical targets for groups of patients sharing the same myeloma-specific chromosomal abnormalities with groups of cell lines.
MM is a plasma cell clonal expansion located within bone marrow in close contact to stromal cells and osteoclasts. Continuous recirculation and spreading of myeloma cells occurs between bone marrow and peripheral blood as soon as diagnosis, implying mechanisms of migration, retention and spreading. PCs are long-lived cells, survival of which is strictly dependent on their retention within bone marrow. Moreover, it is also demonstrated that stromal cells protect myeloma cells, and PCs, from spontaneous and drug-induced cell death. Breaking bone marrow retention appears as an attractive way to increase drug efficiency in vivo. Bone marrow and brain are the most hypoxic organs and the low oxygen concentration is required for maintaining the renewal potential of hematopoietic stem cells.
Our group and others have already demonstrated that osteoclasts as well as stromal cells support the survival of normal and malignant plasma cells. These interactions involve both cell-cell contacts as well as soluble factors.
Mantle cell lymphoma is a B-cell neoplasia involving CD5+ t(11;14) B cells. In this model, the lymphoid environment within lymph nodes or spleen provides cell-mediated interactions supporting retention and survival of tumor cells.
H Enslen, Institut Cochin
Paris T Galli, Centre de Psychiatrie & Neurosciences, Paris
J Goetz, Inserm, Strasbourg H Gronemeyer, IGBMC, Strasbourg
C Hivroz, Institut Curie, Paris
G Pages, IRCAN, Nice
D Ricard, Hôpital d’Instructions des Armées, Percy
RC Glen, Cambridge, UK
MJ Lenardo, NIH, USA
F Sanchez, Valdivia, Chile
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Institut de Recherche en Santé de l'Université de Nantes
8 quai Moncousu