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Kassambara A.,French Institute of Health and Medical Research | Kassambara A.,Montpellier University Hospital Center | Reme T.,French Institute of Health and Medical Research | Reme T.,Montpellier University Hospital Center | And 7 more authors.
PLoS Computational Biology | Year: 2015

DNA microarrays have considerably helped to improve the understanding of biological processes and diseases. Large amounts of publicly available microarray data are accumulating, but are poorly exploited due to a lack of easy-to-use bioinformatics resources. The aim of this study is to build a free and convenient data-mining web site (www.genomicscape.com). GenomicScape allows mining dataset from various microarray platforms, identifying genes differentially expressed between populations, clustering populations, visualizing expression profiles of large sets of genes, and exporting results and figures. We show how easily GenomicScape makes it possible to construct a molecular atlas of the B cell differentiation using publicly available transcriptome data of naïve B cells, centroblasts, centrocytes, memory B cells, preplasmablasts, plasmablasts, early plasma cells and bone marrow plasma cells. Genes overexpressed in each population and the pathways encoded by these genes are provided as well as how the populations cluster together. All the analyses, tables and figures can be easily done and exported using GenomicScape and this B cell to plasma cell atlas is freely available online. Beyond this B cell to plasma cell atlas, the molecular characteristics of any biological process can be easily and freely investigated by uploading the corresponding transcriptome files into GenomicScape. © 2015 Kassambara et al. Source


Kassambara A.,French Institute of Health and Medical Research | Schoenhals M.,French Institute of Health and Medical Research | Moreaux J.,Montpellier University Hospital Center | Veyrune J.-L.,Montpellier University Hospital Center | And 6 more authors.
PLoS ONE | Year: 2013

High throughput DNA microarray has made it possible to outline genes whose expression in malignant plasma cells is associated with short overall survival of patients with Multiple Myeloma (MM). A further step is to elucidate the mechanisms encoded by these genes yielding to drug resistance and/or patients' short survival. We focus here on the biological role of the DEP (for Disheveled, EGL-10, Pleckstrin) domain contained protein 1A (DEPDC1A), a poorly known protein encoded by DEPDC1A gene, whose high expression in malignant plasma cells is associated with short survival of patients. Using conditional lentiviral vector delivery of DEPDC1A shRNA, we report that DEPDC1A knockdown delayed the growth of human myeloma cell lines (HMCLs), with a block in G2 phase of the cell cycle, p53 phosphorylation and stabilization, and p21Cip1 accumulation. DEPDC1A knockdown also resulted in increased expression of mature plasma cell markers, including CXCR4, IL6-R and CD38. Thus DEPDC1A could contribute to the plasmablast features of MMCs found in some patients with adverse prognosis, blocking the differentiation of malignant plasma cells and promoting cell cycle. © 2013 Kassambara et al. Source


Schoenhals M.,French Institute of Health and Medical Research | Kassambara A.,French Institute of Health and Medical Research | Veyrune J.-L.,French Institute of Health and Medical Research | Veyrune J.-L.,Montpellier University Hospital Center | And 7 more authors.
Haematologica | Year: 2013

Krüppel-like factor 4 is a transcription factor with anti-proliferative effects in differentiated cells, but with the ability to reprogram adult cells into cell-cycling pluripotent cells. In cancer, Krüppel-like factor 4 acts as either an antioncogene or an oncogene. We analyzed Krüppel-like factor 4 gene expression in multiple myeloma using Affymetrix microarrays. We generated conditionally expressing Krüppel-like factor 4 myeloma cell lines to investigate the function of this gene in myeloma biology. Krüppel-like factor 4 gene expression is high in normal plasma cells, but reduced in primary multiple myeloma cells from two-thirds of patients. It is not expressed by any human myeloma cell line due to promoter methylation. Conditional expression of Krüppel-like factor 4 led to complete cell cycle blockade, mainly in G1 phase, with no major apoptosis. This blockade was associated with induction of p21Cip1 and p27Kip1 in cell lines with an intact p53 pathway, and of p27Kip1 only in those with an impaired p53 pathway. Krüppel-like factor 4 is highly expressed in the poor prognostic MS group with t(4;14) translocation and in the good prognostic CD-1 group with t(11;14) or t(6;14). The apparent contradiction of cell cycle inhibitor Krüppellike factor 4 expression in patients with poor prognosis could be reconciled since its expression increased the resistance of myeloma cell lines to melphalan. In conclusion, we describe for the first time that Krüppel-like factor 4 could play a critical role in controlling the cell cycle and resistance to alkylating agents in multiple myeloma cells. © 2013 Ferrata Storti Foundation. Source


Kassambara A.,French Institute of Health and Medical Research | Hose D.,Universitatsklinikum Heidelberg And Nationales Centrum For Tumorerkrankungen | Moreaux J.,Montpellier University Hospital Center | Moreaux J.,French Institute of Health and Medical Research | And 8 more authors.
PLoS ONE | Year: 2012

Gene expression-based scores used to predict risk in cancer frequently include genes coding for DNA replication, repair or recombination. Using two independent cohorts of 206 and 345 previously-untreated patients with Multiple Myeloma (MM), we identified 50 cell cycle-unrelated genes overexpressed in multiple myeloma cells (MMCs) compared to normal human proliferating plasmablasts and non-proliferating bone marrow plasma cells and which have prognostic value for overall survival. Thirty-seven of these 50 myeloma genes (74%) were enriched in genes overexpressed in one of 3 normal human stem cell populations - pluripotent (18), hematopoietic (10) or mesenchymal stem cells (9) - and only three genes were enriched in one of 5 populations of differentiated cells (memory B lymphocytes, T lymphocytes, polymorphonuclear cells, monocytes, osteoclasts). These 37 genes shared by MMCs and adult or pluripotent stem cells were used to build a stem cell score (SCscore), which proved to be strongly prognostic in the 2 independent cohorts of patients compared to other gene expression-based risk scores or usual clinical scores using multivariate Cox analysis. This finding highlights cell cycle-unrelated prognostic genes shared by myeloma cells and normal stem cells, whose products might be important for normal and malignant stem cell biology. © 2012 Kassambara et al. Source

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