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Gene expression and methylation profiling of IGHV Unmutated vs mutated CLL

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81937 | GEO | 2017/05/29

SECONDARY ACCESSION(S): PRJNA323462

REPOSITORIES: GEO

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Methylation Profiling of IGHV Unmutated vs mutated CLL

Project description:In the present study, the methylation profiling (MeDIP) was carried out in 14 treatment-naive, early stage (Rai stage 0-2) CLL patients and pooled 19+ normal controls. To find an association of methylation with IGHV mutation status, CLL patients were further segregated into IGHV unmutated (n=9) and IGHV mutated (n=5) subgroups. The methylation signature obtained for CLL versus nornal controls and; unmutated versus mutated CLL was integrated with gene expression profile of these patients and the results were correlated with clinical outcome.

2017-05-29 | GSE81936 | GEO

Gene Expression profiling in IGHV Unmutated vs mutated CLL

Project description:In the present study, the gene expression profiling was carried out in 21 early stage CLL patients. A gene expression signature was generated for CLL patients as compared to normal controls; CLL patients were further seggregated into IGHV unmutated (n=10) and IGHV mutated (n=11) subgroups. The expression pattern was confirmed using real time quantitative PCR and the results were correlated with clinical outcome.

2017-05-29 | GSE81935 | GEO

Gene expression and methylation profiling of IGHV Unmutated vs mutated CLL

Project description:Gene expression and methylation profiling of IGHV Unmutated vs mutated CLL

| PRJNA323462 | ENA

Network analysis reveals a major role for 14q32 cluster miRNAs in determining transcriptional differences between IGHV-mutated and unmutated CLL.

Project description:Chronic lymphocytic leukaemia (CLL) cells can express unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain (IGHV) genes with differing clinical behaviours, variable B cell receptor (BCR) signalling capacity and distinct transcriptional profiles. As it remains unclear how these differences reflect the tumour cells' innate pre/post germinal centre origin or their BCR signalling competence, we applied mRNA/miRNA sequencing to 38 CLL cases categorised into three subsets by IGHV mutational status and BCR signalling capacity. We identified 492 mRNAs and 38 miRNAs differentially expressed between U-CLL and M-CLL, but only 9 mRNAs and 0 miRNAs associated with BCR competence within M-CLL. Of the IGHV-associated miRNAs, (14/38 (37%)) derived from chr14q32 clusters where all miRNAs were co-expressed with the MEG3 lncRNA from a cancer associated imprinted locus. Integrative analysis of miRNA/mRNA data revealed pronounced regulatory potential for the 14q32 miRNAs, potentially accounting for up to 25% of the IGHV-related transcriptome signature. GAB1, a positive regulator of BCR signalling, was potentially regulated by five 14q32 miRNAs and we confirmed that two of these (miR-409-3p and miR-411-3p) significantly repressed activity of the GAB1 3'UTR. Our analysis demonstrates a potential key role of the 14q32 miRNA locus in the regulation of CLL-related gene regulation.

| S-EPMC10317834 | biostudies-literature

IGHV-unmutated and IGHV-mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions.

Project description:Clonal evolution occurs during the course of chronic lymphocytic leukemia (CLL) and activation-induced deaminase (AID) could influence this process. However, this possibility has been questioned in CLL because the number of circulating AID mRNA(+) cells is exceedingly low; synthesis of AID protein by blood CLL cells has not been demonstrated; the full range of AID functions is lacking in unmutated CLL (U-CLL), and no prospective analysis linking AID expression and disease severity has been reported. The results of the present study show that circulating CLL cells and those within secondary lymphoid tissues can make AID mRNA and protein. This production is related to cell division because more AID mRNA was detected in recently divided cells and AID protein was limited to the dividing fraction and was up-regulated on induction of cell division. AID protein was functional because AID(+) dividing cells exhibited more double-stranded DNA breaks, IGH class switching, and new IGHV-D-J mutations. Each of these actions was documented in U-CLL and mutated CLL (M-CLL). Furthermore, AID protein was associated with worse patient outcome and adverse cytogenetics. We conclude that the production of fully functional AID protein by U-CLL and M-CLL cells could be involved in clonal evolution of the disease.

| S-EPMC3520620 | biostudies-literature

Simvastatin and downstream inhibitors circumvent constitutive and stromal cell-induced resistance to doxorubicin in IGHV unmutated CLL cells.

Project description:The immunoglobulin heavy-chain variable region (IGHV) mutational status is a strong determinant of remission duration in chronic lymphocytic leukemia (CLL). The aim of this work was to compare the multidrug resistance (MDR) signature of IGHV mutated and unmutated CLL cells, identifying biochemical and molecular targets potentially amenable to therapeutic intervention.We found that the mevalonate pathway-dependent Ras/ERK1-2 and RhoA/RhoA kinase signaling cascades, and the downstream HIF-1α/P-glycoprotein axis were more active in IGHV unmutated than in mutated cells, leading to a constitutive protection from doxorubicin-induced cytotoxicity. The constitutive MDR phenotype of IGHV unmutated cells was partially dependent on B cell receptor signaling, as shown by the inhibitory effect exerted by ibrutinib. Stromal cells further protected IGHV unmutated cells from doxorubicin by upregulating Ras/ERK1-2, RhoA/RhoA kinase, Akt, HIF-1α and P-glycoprotein activities. Mevalonate pathway inhibition with simvastatin abrogated these signaling pathways and reversed the resistance of IGHV unmutated cells to doxorubicin, also counteracting the protective effect exerted by stromal cells. Similar results were obtained via the targeted inhibition of the downstream molecules ERK1-2, RhoA kinase and HIF-1α.Therefore, targeting the mevalonate pathway and its downstream signaling cascades is a promising strategy to circumvent the MDR signature of IGHV unmutated CLL cells.

| S-EPMC4745766 | biostudies-literature

miRNA expression profile of unmutated and mutated CLL cells

Project description:The aim is to identify the differential miRNA expression profile of B-CLL stimulated with different type of stimulation CPG

2011-06-30 | GSE30106 | GEO

Transcription profiling of human Chronic Lymphocytic Leukemia cells with mutated and unmutated IGHV

Project description:High Expression of Lymphocyte-Activation Gene 3 in Chronic Lymphocytic Leukemia Cells is Associated with Unmutated IGHV and Reduced Treatment-Free Survival

2009-09-17 | E-TABM-696 | biostudies-arrayexpress

miRNA expression profile of unmutated and mutated CLL cells

Project description:The aim is to identify the differential miRNA expression profile of B-CLL stimulated with different type of stimulation CPG One color design, 36 samples, Two-condition experiment, CPG-stimulated B-CLL unmutated and mutated vs. Unstimulated B-CLL unmutated and mutated. Biological replicates: 18 unstimulated replicates, 18 CPG-stimulated replicates.

2011-06-30 | E-GEOD-30106 | biostudies-arrayexpress

Gene expression profile of primary CLL cells transduced with a mutated NOTCH1

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-09-08 | GSE150610 | GEO