Biomedical subjects

Thierry Rème

Publications and source records attributed to Thierry Rème.

6 recordsLinked to original sources

PubMed2006

Microarray-based understanding of normal and malignant plasma cells.

Plasma cells (PCs) develop from B lymphocytes following stimulation by antigen and express a genetic program aimed at the synthesis of immunoglobulins. This program includes the induction of genes coding for transcription factors such as PRDM1, X-box-binding protein 1 and BHLHB3, cell-surface molecules such as CD138/syndecan-1, and for the unfolded protein response. We review how the microarray technology has recently contributed to the understanding of the biology of this rare but essential cell population and its transformation into premalignant and malignant PCs.

B-Lymphocytes↗

PubMed2005

Transcriptional profiles discriminate bone marrow-derived and synovium-derived mesenchymal stem cells.

Previous studies have reported that mesenchymal stem cells (MSC) may be isolated from the synovial membrane by the same protocol as that used for synovial fibroblast cultivation, suggesting that MSC correspond to a subset of the adherent cell population, as MSC from the stromal compartment of the bone marrow (BM). The aims of the present study were, first, to better characterize the MSC derived from the synovial membrane and, second, to compare systematically, in parallel, the MSC-containing cell populations isolated from BM and those derived from the synovium, using quantitative assays. Fluorescent-activated cell sorting analysis revealed that both populations were negative for CD14, CD34 and CD45 expression and that both displayed equal levels of CD44, CD73, CD90 and CD105, a phenotype currently known to be characteristic of BM-MSC. Comparable with BM-MSC, such MSC-like cells isolated from the synovial membrane were shown for the first time to suppress the T-cell response in a mixed lymphocyte reaction, and to express the enzyme indoleamine 2,3-dioxygenase activity to the same extent as BM-MSC, which is a possible mediator of this suppressive activity. Using quantitative RT-PCR these data show that MSC-like cells from the synovium and BM may be induced to chondrogenic differentiation and, to a lesser extent, to osteogenic differentiation, but the osteogenic capacities of the synovium-derived MSC were significantly reduced based on the expression of the markers tested (collagen type II and aggrecan or alkaline phosphatase and osteocalcin, respectively). Transcription profiles, determined with the Atlas Human Cytokine/Receptor Array, revealed discrimination between the MSC-like cells from the synovial membrane and the BM-MSC by 46 of 268 genes. In particular, activin A was shown to be one major upregulated factor, highly secreted by BM-MSC. Whether this reflects a different cellular phenotype, a different amount of MSC in the synovium-derived population compared with BM-MSC adherent cell populations or the impact of a different microenvironment remains to be determined. In conclusion, although the BM-derived and synovium-derived MSC shared similar phenotypic and functional properties, both their differentiation capacities and transcriptional profiles permit one to discriminate the cell populations according to their tissue origin.

Activins↗

PubMed2005

Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells.

A hallmark of plasma cells is the expression of syndecan-1, which has major functions in epithelial cells, in particular as the coreceptor of heparin-binding growth factors. We previously found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a growth factor for malignant plasma cells. As amphiregulin (AREG) is another heparin-binding factor of the EGF family, we investigated its role in multiple myeloma (MM). Using Affymetrix DNA microarrays, we show here that the AREG gene was expressed by purified primary myeloma cells from 65 patients and that the expression was higher than in normal bone marrow (BM) plasma cells or plasmablastic cells. AREG stimulated IL-6 production and growth of BM stromal cells. Using real-time reverse transcriptase-polymerase chain reaction, we found that MM cells expressed ErbB receptors and that AREG promoted their growth. Furthermore, PD169540 (a pan-ErbB inhibitor) and IRESSA (an ErbB1-specific inhibitor) induced apoptosis of primary myeloma cells from 10/14 and 4/14 patients, respectively, and there was a synergistic effect with dexamethasone. Altogether, our data provide strong evidence that AREG plays an important role in the biology of MM and emphasize the advantages of using ErbB inhibitors, which might target myeloma cells as well as the tumor environment.

Amphiregulin↗

PubMed2003

BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone.

Identification of growth factors in neoplasias may be a target for future therapies by blocking either growth factor receptor interaction or the induced pathway. Using gene expression profiling, we identified overexpression of 2 receptors for a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) in malignant plasma cells compared with normal plasma cells. APRIL and BAFF are involved in a variety of tumor and autoimmune diseases, including B-cell malignancies. We confirmed the expression of BAFF and APRIL receptors (B-cell maturation antigen [BCMA], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and BAFF-R) in a majority of 13 myeloma cell lines and in the purified primary myeloma cells of 11 patients. APRIL and BAFF were potent survival factors for exogenous cytokine-dependent myeloma cell lines and were autocrine growth factors for the RPMI8226 and L363 autonomously growing cell lines. These factors activated nuclear factor (NF)-kappaB, phosphatidylinositol-3 (PI-3) kinase/AKT, and mitogen-activated protein kinase (MAPK) kinase pathways and induced a strong up-regulation of the Mcl-1 and Bcl-2 antiapoptotic proteins in myeloma cells. BAFF or APRIL was also involved in the survival of primary myeloma cells cultured with their bone-marrow environment, and protected them from dexamethasone (DEX)-induced apoptosis. Finally, the serum levels of BAFF and APRIL were increased about 5-fold in patients with multiple myeloma (MM) as compared with healthy donors. Altogether, these data suggest that APRIL/BAFF inhibitors may be of clinical value in MM.

Apoptosis↗

PubMed2002

Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays.

The DNA microarray technology enables the identification of the large number of genes involved in the complex deregulation of cell homeostasis taking place in cancer. Using Affymetrix microarrays, we have compared the gene expression profiles of highly purified malignant plasma cells from nine patients with multiple myeloma (MM) and eight myeloma cell lines to those of highly purified nonmalignant plasma cells (eight samples) obtained by in vitro differentiation of peripheral blood B cells. Two unsupervised clustering algorithms classified these 25 samples into two distinct clusters: a malignant plasma cell cluster and a normal plasma cell cluster. Two hundred and fifty genes were significantly up-regulated and 159 down-regulated in malignant plasma samples compared to normal plasma samples. For some of these genes, an overexpression or downregulation of the encoded protein was confirmed (cyclin D1, c-myc, BMI-1, cystatin c, SPARC, RB). Two genes overexpressed in myeloma cells (ABL and cystathionine beta synthase) code for enzymes that could be a therapeutic target with specific drugs. These data provide a new insight into the understanding of myeloma disease and prefigure that the development of DNA microarray could help to develop an 'à la carte' treatment in cancer disease.

Adult↗

PubMed2002

Generation of polyclonal plasmablasts from peripheral blood B cells: a normal counterpart of malignant plasmablasts.

A new way to identify tumor-specific genes is to compare gene expression profiles between malignant cells and their autologous normal counterparts. In patients with multiple myeloma, a major plasma cell disorder, normal plasma cells are not easily attainable in vivo. We report here that in vitro differentiation of peripheral blood B lymphocytes, purified from healthy donors and from patients with multiple myeloma, makes it possible to obtain a homogeneous population of normal plasmablastic cells. These cells were identified by their morphology, phenotype, production of polyclonal immunoglobulins, and expression of major transcription factors involved in B-cell differentiation. Oligonucleotide microarray analysis shows that these polyclonal plasmablastic cells have a gene expression pattern close to that of normal bone marrow-derived plasma cells. Detailed analysis of genes statistically differentially expressed between normal and tumor plasma cells allows the identification of myeloma-specific genes, including oncogenes and genes coding for tumor antigens. These data should help to disclose the molecular mechanisms of myeloma pathogenesis and to define new therapeutic targets in this still fatal malignancy. In addition, the comparison of gene expression between plasmablastic cells and B cells provides a new and powerful tool to identify genes specifically involved in normal plasma cell differentiation.

ADP-ribosyl Cyclase↗