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CSF1R and BTK inhibitions as novel strategies to disrupt the dialogue between mantle cell lymphoma and macrophages

ABSTRACT: CSF1R and BTK inhibitions as novel strategies to disrupt the dialogue between mantle cell lymphoma and macrophages

PROVIDER: PRJNA514336 | ENA |

REPOSITORIES: ENA

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CSF1R and BTK inhibitions as novel strategies to disrupt the dialogue between mantle cell lymphoma and macrophages

Project description:The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. We focused on the interplay between MCL cells and associated monocytes/macrophages.

2019-08-27 | GSE124931 | GEO

The BTK Inhibitor CC-292 shows activity in Mantle Cell Lymphoma and synergizes with Lenalidomide and NIK Inhibitors depending on NFκB mutational status

Project description:Mantle Cell lymphoma (MCL) were treated with the BTK inhibitor 1mM CC-292 for 48h We used microarrays to uncover the mechanisms underlying CC-292 activity in Mantle Cell lymphoma (MCL)

2017-09-01 | GSE94328 | GEO

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

CD52 and OXPHOS - potential targets in ibrutinib treated mantle cell lymphoma

Project description:We performed a RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line treated with ibrutinib for up to 4 d to study transcriptomic adaptations to the BTK inhibitor in surviving cells.

2022-12-22 | GSE214725 | GEO

Allosteric inhibition of proteolytic and ATPase activities of the proteasome by the BTK inhibitor CGI-1746

Project description:Bruton’s tyrosine kinase (BTK) inhibitor Ibrutinib has been shown to synergize in vitro with proteasome inhibitors (PIs) in reducing the viability of cells derived from B-cell malignancies, but the mechanism is not known. We report here that an off-target effect of Ibrutinib causes synergy because not all BTK inhibitors exhibited the synergistic effect, and those that synergized did so even in cells that do not express BTK. The allosteric BTK inhibitor CGI-1746 showed the strongest synergy. Co-treatment of cells with CGI-1746 increased PI-induced expression of heat shock proteins and accumulation of ubiquitin conjugates. The CGI-1746 inhibited the degradation of a model substrate by a purified 26S proteasome. CGI-1746, but not other BTK inhibitors, allosterically inhibited ATPase activity and 2 and 1 peptidase activities of the 26S proteasomes. Although the effect is unlikely to contribute to the anti-neoplastic activity of BTK inhibitors in multiple myeloma and mantle cell lymphoma, it demonstrates a conceptually novel mode of inhibition that may aid the development of more potent proteasome inhibitors and improve response in solid tumors clinically.

2023-08-01 | GSE239482 | GEO

Synergistic activity of BET protein antagonist-based combinations in Mantle Cell Lymphoma cells sensitive or resistant to ibrutinib

Project description:To determine the global transcriptome changes in mantle cell lymphoma cells following treatment with the BET bromodomain antagonist, JQ1 Mantle Cell Lymphoma (MCL) cells exhibit increased B cell receptor and NFkB activities. The BET protein BRD4 is essential for the transcriptional activity of NFkB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and CDK4/6, inhibits the nuclear RelA levels and the expression of NFÎºB target genes including Brutonâs Tyrosine Kinase (BTK) in MCL cells. While lowering the levels of the anti-apoptotic BCL2 family proteins, BA treatment induces the pro-apoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Co-treatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared to each agent alone, co-treatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells which overexpress CDK6, BCL2, Bcl-xL, XIAP and AKT, but lack ibrutinib resistance-conferring BTK mutation. Co-treatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. MO2058 cells treated with vehicle, 250 nM or 1000 nM JQ1 for 8 hours. Samples were acquired and analyzed in duplicate.

2015-12-31 | E-GEOD-70651 | biostudies-arrayexpress

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

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

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

Cell Cycle Reprogramming for PI3K Inhibition Overrides Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma

Project description:The RNA-seq data presented in this study include libraries from Mantle Cell Lymphoma (MCL) tumor cells sequentially obtained from patients

2017-02-25 | GSE55405 | GEO

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