Lasting B-cell persistence depends on survival signals that are transduced by cell surface receptors. Here, we describe a novel biological mechanism essential for survival and homeostasis of normal peripheral mature B cells and chronic lymphocytic leukemia (CLL) cells, regulated by the heparin-binding cytokine, midkine (MK), and its proteoglycan receptor, the receptor-type tyrosine phosphatase zeta (RPTP). We demonstrate that MK initiates a signaling cascade leading to B cell survival, by binding to RPTP. In mice lacking PTPRZ, the proportion and number of the mature B cell population is reduced. Our results emphasize a unique and critical function for MK signaling in the previously described MIF/CD74 induced survival pathway. Stimulation of CD74 with MIF leads to c-Met activation, resulting in elevation of MK expression in both normal mouse splenic B and CLL cells. Our results indicate that MK and RPTP are important regulators of the B cell repertoire. These findings could pave the way towards understanding the mechanisms shaping B cell survival, and suggest novel therapeutic strategies based on the blockade of the midkine/RPTP-dependent survival pathway.
The cytokine midkine and its receptor RPTPζ regulate B cell survival in a pathway induced by CD74.
Age
View SamplesChronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B lymphocytes in peripheral blood, lymphoid organs and BM. The main feature of the disease is accumulation of the malignant cells due to decreased apoptosis. CD84 belongs to the Signaling Lymphocyte Activating Molecule (SLAM) family of immunoreceptors, and has an unknown function in CLL cells. Here, we show that the expression of CD84 is significantly elevated from the early stages of the disease, and is regulated by macrophage migration inhibitory factor (MIF) and its receptor, CD74. Activation of cell surface CD84 initiates a signaling cascade that enhances CLL cell survival. Both immune-mediated neutralization or blockade of CD84 induce cell death in vitro and in vivo. In addition, analysis of samples derived from an on-going clinical trial, in which human subjects were treated with humanized anti-CD74 milatuzumab shows a decrease in CD84 mRNA levels milatuzumab-treated cells. This downregulation was correlated with reduction of Bcl-2 and Mcl-1 message. Thus, our data show that overexpression of CD84 in CLL is an important survival mechanism that appears to be an early event in the pathogenesis of the disease. These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.
CD84 is a survival receptor for CLL cells.
Disease
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Integrative genomic analysis of the human immune response to influenza vaccination.
Sex, Specimen part, Treatment, Subject, Time
View SamplesThe purpose of the study was to assess the patterns of global gene expression in peripheral blood cells before and at three time points after the administration of a trivalent influenza vaccine in human male subjects, and to relate these to the antibody response to the vaccine. The antibody titer data for these subjects is provided as a supplemental file.
Integrative genomic analysis of the human immune response to influenza vaccination.
Sex, Specimen part, Treatment, Subject, Time
View SamplesThe purpose of the study was to assess the patterns of global gene expression in peripheral blood cells before and at three time points after the administration of a trivalent influenza vaccine in human female subjects, and to relate these to the antibody response to the vaccine
Integrative genomic analysis of the human immune response to influenza vaccination.
Sex, Specimen part, Treatment, Subject, Time
View SamplesBackground: The prefrontal cortex is important in regulating sleep and mood. Diurnally regulated genes in the prefrontal cortex may be controlled by the circadian system, by the sleep-wake states, or by cellular metabolism or environmental responses. Bioinformatics analysis of these genes will provide insights into a wide-range of pathways that are involved in the pathophysiology of sleep disorders and psychiatric disorders with sleep disturbances. Results: We examined gene expression in the mouse prefrontal cortex at four time points during the 24-hour (12-hour light:12-hour dark) cycle by microarrays, and identified 3,890 transcripts corresponding to 2,927 genes with diurnally regulated expression patterns. We show that 16% of the genes identified in our study are orthologs of identified clock, clock controlled or sleep/wakefulness induced genes in the mouse liver and SCN, rat cortex and cerebellum, or Drosophila head. The diurnal expression patterns were confirmed in 16 out of 18 genes in an independent set of RNA samples. The diurnal genes fall into eight temporal categories with distinct functional attributes, as assessed by the Gene Ontology classification and by the analysis of enriched transcription factor binding sites. Conclusions: Our analysis demonstrates that ~10% of transcripts have diurnally regulated expression patterns in the mouse prefrontal cortex. Functional annotation of these genes will be important for the selection of candidate genes for behavioural mutants in the mouse and for genetic studies of disorders associated with anomalies in the sleep:wake cycle and circadian rhythms.
Genome-wide expression profiling and bioinformatics analysis of diurnally regulated genes in the mouse prefrontal cortex.
No sample metadata fields
View SamplesFibroblasts and lymphoblastoid cells (LCLs) are the most widely used cells in genetic, genomic, and transcriptomic studies in relation to human diseases. Examining the gene expression patterns in these two cell types will provide valuable information regarding the validity of using them to study gene expression related to various human diseases.
Genomic landscape of a three-generation pedigree segregating affective disorder.
Age, Disease
View SamplesThe wheat gene Lr34 (Yr18/Pm38/Sr57/Ltn1) encodes a putative ABCG-type of transporter and is a unique source of disease resistance providing durable and partial resistance against multiple fungal pathogens. Lr34 has been found to be functional as a transgene in barley.
The wheat resistance gene Lr34 results in the constitutive induction of multiple defense pathways in transgenic barley.
Specimen part
View SamplesPurpose: We tested global gene transcriptome changes by RNA-sequencing analysis in the offspring breast tumors of SV40 transgenic mice to further identify key epigenetic-controlled genes in regulation of the prenatal/maternal BSp diet-mediated early breast cancer prevention. Method: Mouse offspring mammary tumor mRNA from control and maternal BSp treatment were generated by deep sequencing, in duplicate or triplicate, using Illumina NextSeq500 platform (GPL19057). The sequence reads that passed quality filters were analyzed. We utilized the R/Bioconductor package DESeq to evaluate differential gene expression for sequence count data by the use of negative binomial distributio. qRT–PCR validation was performed using TaqMan and SYBR Green assays. Conclusions: Our data showed differential transcriptome distribution in the breast tumors of mouse offspring between the control and prenatal/maternal BSp treatment groups. Overall design: Total RNA obtained from the offspring breast tumors of SV40 transgenic mice with mothers fed either control or BSp diets, and analyzed by Illumina NextSeq500 platform (GPL19057).
Temporal Efficacy of a Sulforaphane-Based Broccoli Sprout Diet in Prevention of Breast Cancer through Modulation of Epigenetic Mechanisms.
Age, Cell line, Treatment, Subject
View SamplesDue to limited bio-availability of Fe, plants evolved adaptive alterations in development regulated at the transcriptional level. We investigated the early transcriptional response to Fe deficiency.
Early iron-deficiency-induced transcriptional changes in Arabidopsis roots as revealed by microarray analyses.
Specimen part
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