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Kinome profiling of primary CLL cells

ABSTRACT: Investigation of BCR signalling response of primary cells from a cohort of 40 CLL patients using kinobbead idolation and MS profiling. Cells were either stimulated using anti-IgM or isotype control.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Blood

SUBMITTER: Adam Linley

LAB HEAD: Adam Linley

PROVIDER: PXD027131 | Pride | 2023-03-11

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	CLL10_IC.raw	Raw
	CLL10_IGM.raw	Raw
	CLL11_IC.raw	Raw
	CLL11_IGM.raw	Raw
	CLL12_IC.raw	Raw

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Publications

Kinobead Profiling Reveals Reprogramming of BCR Signaling in Response to Therapy within Primary CLL Cells.

Linley Adam J AJ Karydis Laura I LI Mondru Anil K AK D'Avola Annalisa A Al Shmrany Humood H Cicconi Silvia S Griffin Rebecca R Forconi Francesco F Pettitt Andrew R AR Kalakonda Nagesh N Rawstron Andrew C AC Hillmen Peter P Steele Andrew J AJ MacEwan David J DJ Packham Graham G Prior Ian A IA Slupsky Joseph R JR

Clinical cancer research : an official journal of the American Association for Cancer Research 20210811 20

<h4>Purpose</h4>B-cell receptor (BCR) signaling is critical for the pathogenesis of chronic lymphocytic leukemia (CLL), promoting both malignant cell survival and disease progression. Although vital, understanding of the wider signaling network associated with malignant BCR stimulation is poor. This is relevant with respect to potential changes in response to therapy, particularly involving kinase inhibitors. In the current study, we describe a novel high-resolution approach to investigate BCR s ...[more]

PMID: 34380642

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Gene expression study in CLL of B-cell receptor triggering (miRNA study)

Project description:The B-cell receptor (BCR) plays an important role in pathogenesis and progression of chronic lymphocytic leukemia (CLL). We investigated the BCR triggering-dependent microRNA modulation by stimulating CLL cells with immobilized anti-IgM. miRome of immobilized anti-IgM stimulated CLL cells (n=16) identified a substantial upregulation of miR-132 in both unmutated (UM) and mutated (M) IGHV subgroups. A parallel gene expression profile and an in-silico analysis to identify miR-132 target genes¸ allowed us to focus on SIRT1, that encodes for a histone deacetylase targeting several proteins including TP53. We defined a reduction of SIRT1 protein levels upon immobilized anti-IgM stimulation (P=0.001), and a concomitant increase in TP53 acetylation (P=0.0072). The TP53 target gene CDKN1A was consistently up-regulated in immobilized anti-IgM stimulated CLL cells. Of note, the miR-132 constitutive expression levels in CLL cases (n=134) were of similar magnitude of those obtained in in vitro immobilized anti-IgM stimulated CLL cells. Additionally, high miR-132 expression levels retained a favorable prognostic impact in M (P=0.005), but not in UM CLL patients (P=0.968). The described miR-132/SIRT1/TP53 axis, sequentially characterized by BCR triggering, miR-132 up-regulation, SIRT1 down-regulation and TP53 acetylation, should be considered in the light of emerging drugs targeting the BCR pathway in CLL. investigated the BCR triggering-dependent gene expression modulation by stimulating CLL cells with immobilized anti-IgM.

2014-01-01 | E-GEOD-52775 | biostudies-arrayexpress

Gene expression study in CLL of B-cell receptor triggering (mRNA Study)

Project description:The B-cell receptor (BCR) plays an important role in pathogenesis and progression of chronic lymphocytic leukemia (CLL). We investigated the BCR triggering-dependent mRNA modulation by stimulating CLL cells with immobilized anti-IgM. miRome of immobilized anti-IgM stimulated CLL cells (n=16) identified a substantial upregulation of miR-132 in both unmutated (UM) and mutated (M) IGHV subgroups. A parallel gene expression profile and an in-silico analysis to identify miR-132 target genesÂ¸ allowed us to focus on SIRT1, that encodes for a histone deacetylase targeting several proteins including TP53. We defined a reduction of SIRT1 protein levels upon immobilized anti-IgM stimulation (P=0.001), and a concomitant increase in TP53 acetylation (P=0.0072). The TP53 target gene CDKN1A was consistently up-regulated in immobilized anti-IgM stimulated CLL cells. Of note, the miR-132 constitutive expression levels in CLL cases (n=134) were of similar magnitude of those obtained in in vitro immobilized anti-IgM stimulated CLL cells. Additionally, high miR-132 expression levels retained a favorable prognostic impact in M (P=0.005), but not in UM CLL patients (P=0.968). The described miR-132/SIRT1/TP53 axis, sequentially characterized by BCR triggering, miR-132 up-regulation, SIRT1 down-regulation and TP53 acetylation, should be considered in the light of emerging drugs targeting the BCR pathway in CLL. Investigated the BCR triggering-dependent gene expression modulation by stimulating CLL cells with immobilized anti-IgM.

2014-01-01 | E-GEOD-52774 | biostudies-arrayexpress

Gene expression study in CLL of B-cell receptor triggering (miRNA study)

2014-01-01 | GSE52775 | GEO

Gene expression study in CLL of B-cell receptor triggering (mRNA Study)

Project description:The B-cell receptor (BCR) plays an important role in pathogenesis and progression of chronic lymphocytic leukemia (CLL). We investigated the BCR triggering-dependent mRNA modulation by stimulating CLL cells with immobilized anti-IgM. miRome of immobilized anti-IgM stimulated CLL cells (n=16) identified a substantial upregulation of miR-132 in both unmutated (UM) and mutated (M) IGHV subgroups. A parallel gene expression profile and an in-silico analysis to identify miR-132 target genes¸ allowed us to focus on SIRT1, that encodes for a histone deacetylase targeting several proteins including TP53. We defined a reduction of SIRT1 protein levels upon immobilized anti-IgM stimulation (P=0.001), and a concomitant increase in TP53 acetylation (P=0.0072). The TP53 target gene CDKN1A was consistently up-regulated in immobilized anti-IgM stimulated CLL cells. Of note, the miR-132 constitutive expression levels in CLL cases (n=134) were of similar magnitude of those obtained in in vitro immobilized anti-IgM stimulated CLL cells. Additionally, high miR-132 expression levels retained a favorable prognostic impact in M (P=0.005), but not in UM CLL patients (P=0.968). The described miR-132/SIRT1/TP53 axis, sequentially characterized by BCR triggering, miR-132 up-regulation, SIRT1 down-regulation and TP53 acetylation, should be considered in the light of emerging drugs targeting the BCR pathway in CLL.

2014-01-01 | GSE52774 | GEO

Expression data from healthy and malignant (chronic lymphocytic leukemia, CLL) human B-lymphocytes after B-cell receptor stimulation

Project description:Three different cell populations (6 healthy B-lymphocytes, 6 leukemic CLL B-lymphocyte of indolent form and 5 leukemic CLL B-lymphocyte of aggressive form) were stimulated in vitro with an anti-IgM antibody, activating the B-cell receptor (BCR). We analyzed the gene expression at 4 time points (60, 90, 210 and 390 minutes). Each gene expression measurement is performed both in stimulated cells and in control unstimulated cells. For one aggressive CLL case, we silenced expression of DUSP1 by transfecting DUSP1-specific RNAi and, as a control, transfected cells with a non-targeting RNAi. We then stimulated the BCR of these cells and analyzed the gene expression at the same time points in stimulated cells and in control unstimulated cells. B-cells were negatively selected from healthy donors and previously untreated CLL patients. BCR stimulated and unstimulated control B-cells were treated at four time points after stimulation for total RNA extraction and hybridization on Affymetrix microarrays.

2013-01-04 | E-GEOD-39411 | biostudies-arrayexpress

Identification and functional annotation of the Src-regulated kinome, part 2

Project description:Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. Herein, we describe a novel, integrated approach that addresses this knowledge gap. This utilizes mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotates the regulated kinases. As an example, we identified approximately one hundred protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. Screening with corresponding siRNAs identified nine kinases, including SGK1, as being essential for Src-induced transformation. In contrast, MAP4K5 suppressed transformation in a manner enhanced by S335 phosphorylation. In triple negative breast cancer cells, Src positively regulated SGK1 expression and combined inhibition of Src and SGK1 was more effective at inhibiting cell proliferation than either treatment alone. Therefore, this approach not only provides major mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.

2018-11-21 | PXD011146 | Pride

Expression data from healthy and malignant (chronic lymphocytic leukemia, CLL) human B-lymphocytes after B-cell receptor stimulation

2013-01-04 | GSE39411 | GEO

Increased CLL Proliferation upon IgM stimulation is Sustained by the Up-regulation of miR-132 and miR-212: a Combined miRNA and Gene Expression Profiling Analysis and Correlation with Disease Progression [gene expression]

Project description:In order to investigate a potential involvement of miRNAs in BCR stimulation, in the present work we first evaluated their expression following IgM cross-linking in CLL cells, as well as in healthy B lymphocytes. Next, to infer putative miRNA targeting networks, we combined miRNA profiling results with gene expression and functional analyses Gene expression profiling analysis by microarray analysis of CLL samples.

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Gene expression profile of primary CLL cells transduced with a mutated form on NOTCH1 following IgM stimulation

Project description:In CLL, NOTCH1 is the most commonly mutated gene at diagnosis and it is associated with a poor outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. Data suggests a link between BCR activation and NOTCH1 signalling so the main goal of this study is to compare the gene expression profile of primary CLL cells transduced with the intracellular part of NOTCH1 lacking of the PEST domain vs cells transduced with an empty vector following IgM stimulation.

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Project description:In order to investigate a potential involvement of miRNAs in BCR stimulation, in the present work we first evaluated their expression following IgM cross-linking in CLL cells, as well as in healthy B lymphocytes. Next, to infer putative miRNA targeting networks, we combined miRNA profiling results with gene expression and functional analyses miRNA expression profiling analysis by microarray analysis of CLL samples and pools of CD19+ cells derived from healthy donors.

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