TY - JOUR
T1 - Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data
AU - Schrader, Alexandra
AU - Meyer, Katharina
AU - Walther, Neele
AU - Stolz, Ailine
AU - Feist, Maren
AU - Hand, Elisabeth
AU - von Bonin, Frederike
AU - Evers, Maurits
AU - Kohler, Christian
AU - Shirneshan, Katayoon
AU - Vockerodt, Martina
AU - Klapper, Wolfram
AU - Szczepanowski, Monika
AU - Murray, Paul G
AU - Bastians, Holger
AU - Trümper, Lorenz
AU - Spang, Rainer
AU - Kube, Dieter
PY - 2016/5/7
Y1 - 2016/5/7
N2 - To discover new regulatory pathways in B lymphoma cells, we performed a combined analysis of experimental, clinical and global gene expression data. We identified a specific cluster of genes that was coherently expressed in primary lymphoma samples and suppressed by activation of the B cell receptor (BCR) through αIgM treatment of lymphoma cells in vitro. This gene cluster, which we called BCR.1, includes numerous cell cycle regulators. A reduced expression of BCR.1 genes after BCR activation was observed in different cell lines and also in CD10+ germinal center B cells. We found that BCR activation led to a delayed entry to and progression of mitosis and defects in metaphase. Cytogenetic changes were detected upon long-term αIgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc co-regulated genes in distinct groups of lymphoma patients was observed. Finally, we showed that the BCR.1 index discriminates activated B cell-like and germinal centre B cell-like diffuse large B cell lymphoma supporting the functional relevance of this new regulatory circuit and the power of guided clustering for biomarker discovery.
AB - To discover new regulatory pathways in B lymphoma cells, we performed a combined analysis of experimental, clinical and global gene expression data. We identified a specific cluster of genes that was coherently expressed in primary lymphoma samples and suppressed by activation of the B cell receptor (BCR) through αIgM treatment of lymphoma cells in vitro. This gene cluster, which we called BCR.1, includes numerous cell cycle regulators. A reduced expression of BCR.1 genes after BCR activation was observed in different cell lines and also in CD10+ germinal center B cells. We found that BCR activation led to a delayed entry to and progression of mitosis and defects in metaphase. Cytogenetic changes were detected upon long-term αIgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc co-regulated genes in distinct groups of lymphoma patients was observed. Finally, we showed that the BCR.1 index discriminates activated B cell-like and germinal centre B cell-like diffuse large B cell lymphoma supporting the functional relevance of this new regulatory circuit and the power of guided clustering for biomarker discovery.
KW - B-Lymphocytes/metabolism
KW - Cell Cycle/genetics
KW - Cell Line, Tumor
KW - Cohort Studies
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Gene Regulatory Networks
KW - Germinal Center/metabolism
KW - Humans
KW - Lymphocyte Activation
KW - Lymphoma, Large B-Cell, Diffuse/genetics
KW - Proto-Oncogene Proteins c-bcl-6
KW - Proto-Oncogene Proteins c-myc
KW - Receptors, Antigen, B-Cell/genetics
KW - Signal Transduction/genetics
KW - Tumor Microenvironment
U2 - 10.18632/oncotarget.9219
DO - 10.18632/oncotarget.9219
M3 - Article
C2 - 27166259
SN - 1949-2553
VL - 7
SP - 47061
EP - 47081
JO - OncoTarget
JF - OncoTarget
IS - 30
ER -