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FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma

ABSTRACT: Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to identify BTK targets by RNA-seq and high-throughput data analysis and verify these genes by quantitative reverse transcription polymerase chain reaction (qRT–PCR) methods Methods: mino/z138 sc4/shbtk stable cell lines were generated with tet-on system vector, small hairpins were induced for 48 hours after doxycycline addition, mRNA was exacted and used for RNA sequencing. After TopHat analysis followed by Cufflinks, down/up regulated genes list was generated. qRT–PCR validation was then performed using SYBR Green assays Results: Using an optimized data analysis workflow and with a fold change ≥1.3 and p value <0.05, thousands of genes were changed. Altered expression of 6 genes was then confirmed with qRT–PCR, demonstrating the high qulity of the RNA-seq method.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80563 | GEO | 2016/04/23

SECONDARY ACCESSION(S): PRJNA319310

REPOSITORIES: GEO

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FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma.

Project description:Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.

| S-EPMC5102814 | biostudies-literature

Gene expression profile in B cells from Xid and Btk KO mice

Project description:Bruton's tyrosine kinase (Btk) is important for B lymphocyte development. To identify genes that are differentially expressed in primary B cells lacking functional Btk, splenocytes from X-linked immunodeficiency (Xid), Btk knockout (KO) and immunocompetent CBA mice, were used in microarrays containing more than 12,000 genes and expressed sequence tags (ESTs). We found 4515 transcripts expressed in duplicate experiments in all three strains. Out of these, 38 were differentially expressed genes (21 up-regulated >2 fold and 17 down-regulated <-2 fold) between CBA and Btk defective mice. Ten out of these genes were selected and quantitative Real-Time PCR was conducted for validation and further investigation. Real-Time experiments correlated nicely with the microarray data. No definitive phenotypic difference has previously been reported between Xid and Btk KO mice. We found 7 genes, whose expression differed (>2 fold) between the two strains. Moreover, when the 38 genes, which differed between immunocompetent CBA and Btk defective mice were ranked according to fold-increase, the levels in Btk KO mice were significantly more altered. This suggests that the defect in Btk KO mice is more severe and demonstrates that the mutant Btk protein in Xid mice does not generally function as dominant negative form. Keywords: Btk, DNA microarray, Xid, Btk KO, Real-Time PCR

2005-06-21 | GSE2826 | GEO

Transcription profiling of B cells from Xid mice, Btk knockout and CBA mice to identify genes that are differentially expressed in primary B cells lacking functional Btk gene.

Project description:Bruton's tyrosine kinase (Btk) is important for B lymphocyte development. To identify genes that are differentially expressed in primary B cells lacking functional Btk, splenocytes from X-linked immunodeficiency (Xid), Btk knockout (KO) and immunocompetent CBA mice, were used in microarrays containing more than 12,000 genes and expressed sequence tags (ESTs). We found 4515 transcripts expressed in duplicate experiments in all three strains. Out of these, 38 were differentially expressed genes (21 up-regulated >2 fold and 17 down-regulated <-2 fold) between CBA and Btk defective mice. Ten out of these genes were selected and quantitative Real-Time PCR was conducted for validation and further investigation. Real-Time experiments correlated nicely with the microarray data. No definitive phenotypic difference has previously been reported between Xid and Btk KO mice. We found 7 genes, whose expression differed (>2 fold) between the two strains. Moreover, when the 38 genes, which differed between immunocompetent CBA and Btk defective mice were ranked according to fold-increase, the levels in Btk KO mice were significantly more altered. This suggests that the defect in Btk KO mice is more severe and demonstrates that the mutant Btk protein in Xid mice does not generally function as dominant negative form. Experiment Overall Design: 6 Affymetrix U74Av2 GeneChip arrays was run. Three initially with CBA, Xid and Btk KO mice and then additional three chips with new RNA preperations from new CBA, Xid and Btk KO mice.

2007-08-31 | E-GEOD-2826 | biostudies-arrayexpress

Combining BTK inhibitors with BCL2 inhibitors for treating chronic lymphocytic leukemia and mantle cell lymphoma.

Project description:The advent of BTK inhibitors has changed the treatment of patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The first-in-class BTK inhibitor ibrutinib has shown remarkable therapeutic effects and manageable toxicities in multiple clinical trials. The second-generation BTK inhibitors, including acalabrutinib and zanubrutinib, also show remarkable efficacies. However, using BTK inhibitors as monotherapies requires continuous treatment. Resistance to BTK inhibitors and severe side effects unavoidably occur during BTK inhibitor monotherapy, frequently resulting in treatment failure. The addition of the BCL2 inhibitor venetoclax to BTK inhibitor may improve the therapeutic effects and result in deeper responses, providing a potential fixed-duration treatment, especially for patients with CLL. In this review, by focusing on CLL and MCL, we discussed the rationale for the combinational use and summarized the current data on the combinations of BTK inhibitors and venetoclax in patients with CLL and MCL.

| S-EPMC8981798 | biostudies-literature

Modeling the clinical phenotype of BTK inhibition in the mature murine immune system

Project description:Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. While BTK inhibition does not impact humoral memory survival, antigen-driven clonal expansion of memory B cells and antibody secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of BTK inhibition. We used Affymetrix genechips to profile the transcriptional changes downstream of BTK inhibition after in vivo B-cell activation by anti-IgD Mice were injected with the novel BTK inhibitor PF-303 2 hours prior to anti-IgD mediated in vivo B-cell activation; B-cells where harvested 2 hours after anti-IgD activation and RNA isolated.

2014-08-01 | E-GEOD-56483 | biostudies-arrayexpress

Dual BTK/SYK inhibition with CG-806 disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma

Project description:We show the impacts of the BTK/SYK inhibitor CG806 on RNA-seq gene expression in mice xenografted with Mantle Cell Lymphoma

2021-04-27 | GSE173353 | GEO

NR4A1 Inhibition Synergizes with Ibrutinib in Killing Mantle Cell Lymphoma Cells

Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to identify NR4A1 targets by RNA-seq and high-throughput data analysis and verify these genes by quantitative reverse transcription polymerase chain reaction (qRT–PCR) methods. Methods: Jeko/Rec-1 Cas9 control and NR4A1 sgRNA stable cell lines were generated with tet-on system vector, sg RNAs were induced for 48 hours after doxycycline addition, mRNA was extracted and used for RNA sequencing. After TopHat analysis followed by Cufflinks, down/up regulated genes list was generated. qRT–PCR validation was then performed using SYBR Green assays. Results: Using an optimized data analysis workflow and with a fold change ≥1.3 and p value <0.05, thousands of genes were changed. Altered expression of 6 genes was then confirmed with qRT–PCR, demonstrating the high qulity of the RNA-seq method.

2017-10-25 | GSE106092 | GEO

Proteomics of Btk haemolymph stimulon

Project description:The spore-forming bacterium Bacillus thuringiensis (Bt) of B. cereus group uses toxin-opened breaches at the insect midgut epithelium to infest the haemolymph where it rapidly propagates despite antimicrobial host defences to induce eventually host death by acute septicaemia. The response of Bt to haemolymph and the latter’s role in bacterial pathogenesis is an area that needs clarification. We report the proteome analysis of Bt subsp. kurstaki (Btk) haemolymph stimulon consisted of significant changes in 60 (34 up- and 26 down-regulated) differentially accumulated proteins (DAPs). Gene Ontology (GO) enrichment analysis revealed Btk haemolymph-responsive DAPs were mainly involved in glutamate metabolism, transketolase activity and ATP-dependent transmembrane transporters. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis disclosed that DAPs were highly enriched in enzymes related to the biosynthesis of ansamycins, a family of bacterial polyketides with antimicrobial activity. Interestingly, around 30% of DAPs were putative virulence factors, including polyketide synthase, ABC transporter, and cytotoxin. Collectively, our findings suggest Btk haemolymph stimulon could be partially driven bacterial survival and propagation within the haemolymph of infected insects, contributing to its remarkable success as entomopathogen.

2021-11-02 | PXD021830 | Pride

BTK drives neutrophil activation for sterilizing antifungal immunity

Project description:We describe a previously unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcgR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment nor lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.

2024-05-17 | GSE243974 | GEO

Role of IL-2 inducible T cell kinase (ITK) and Bruton's tyrosine kinase (BTK) in mast cell response to lipopolysaccharide (LPS)

Project description:Mast cells are indispensable for LPS-induced septic hypothermia, in which TNF-Î± plays an essential role to initiate sepsis. Tec family non-receptor tyrosine kinases ITK and BTK regulate mast cell-derived TNF-Î± in response to allergic antigen, but their role in LPS-induced TNF-Î± production by mast cells and related pathology is unclear. We sought to investigate the role(s) of ITK and BTK in mast cell response in septic condition. We found that the absence of ITK and BTK leads to enhanced TNF-Î± production by bone marrow-derived mast cells (BMMC). Itk-/-Btk-/- mast cells exhibit hyperactive preformed and LPS-induced TNF-Î± production, along with enhanced expression of other related genes such as NF-ÎºB targeted genes, compared to WT cells. Bone marrow cells from 8-week old WT, Itk-/-, Btk-/- and Itk-/-Btk-/- (double knockout: DKO) C57Bl/6 mice were cultured in murine Interleukin-3/Stem cell factor (IL-3/SCF) supplemented medium for 5 weeks to derive mast cells. WT, Itk-/-, Btk-/- and DKO bone marrow-derived mast cells (BMMC) were factor starved in medium without IL-3/SCF for 12 hours, followed by treatment with PBS (control) or 100 ng/ml LPS for 1 hour. Triplicates of each group were subjected to mouse whole genome genechip microarray analysis. Replicates were randomized on different chips to avoid systematic error.

2015-11-23 | E-GEOD-64287 | biostudies-arrayexpress

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