Project description:In this study we investigated changes in gene expression induced by 2cPE (a non-selective isopeptidase inhibitor) in leukemia cells isolated from 10 different patients suffering of B-cell chronic lymphocytic leukemia. We compared 2cPE induced changes in mRNA levels with those induced by bortezomib, another well characterized proteasome inhibitor. Both inhibitors trigger apoptosis in leukemia cells.
Project description:Chronic lymphocytic leukemia (CLL) B-cells receive signals from the lymph node and bone marrow (BM) microenvironments that regulate their survival and proliferation. These signals and the pathways that propagate them to the interior of the cell represent potential targets for therapeutic intervention. To characterize the pathways that are activated by the BM microenvironment in CLL cells in vivo, we performed gene expression profiling of tumor cells purified from BM and peripheral blood. Functional classification analysis revealed that the most frequently upregulated genes in BM-CLL cells are genes involved in cell cycle and mitosis. Among the most significantly overexpressed were the Aurora A and B kinases. To investigate whether these kinases could represent potential therapeutic targets in CLL, we performed RNA interference experiments in the CLL cell lines MEC1 and EHEB. Downregulation of Aurora A and B inhibited the proliferation and induced apoptosis in these cells. Similar effects were observed with the pan-Aurora kinase inhibitor VX-680 in primary CLL cells induced to proliferate by CpG-ODN and IL-2. VX-680 also inhibited leukemia growth in vivo in a mouse model of CLL. These data suggest that inhibition of Aurora kinases could represent a potential strategy to selectively target the proliferating compartment in CLL. To identify gene expression related to microenvironmental stimuli in B-cell Chronic Lymphocytic Leukemia (CLL) cells in vivo, expression profiles of CLL cells purified (>95%) from bone marrow (BM) and peripheral blood (PB) were compared. Paired BM and PB samples from 6 individuals were used for this analysis.
Project description:This SuperSeries is composed of the following subset Series:; GSE10137: A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia (Mayo_Ohio); GSE10138: A Genomic Approach to Improve Prognosis and Predict Therapeutic Response in Chronic Lymphocytic Leukemia (Duke_VA) Experiment Overall Design: Refer to individual Series
Project description:Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant CD5+ B lymphocytes (CLL cells) in the peripheral blood, and their progressive infiltration in lymphoid organs. MMP-9 plays an important role in cell migration and survival, contributes to CLL pathogenesis by proteolytic and non-proteolytic mechanisms and may constitutive a therapeutic target. We used Affimetrix microarray technology to characterize the global gene expression profile of chronic lymphocytic leukemia (CLL) cells upon MMP-9 transfection. The aim was to establish whether MMP-9 regulates gene expression and to identify new therapeutic targets in CLL.
