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Transcriptional reprogramming in mantle cell lymphoma promotes BTK inhibitor resistance

ABSTRACT: Transcriptional reprogramming in mantle cell lymphoma promotes BTK inhibitor resistance

PROVIDER: PRJNA1304501 | ENA |

REPOSITORIES: ENA

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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

Transcriptional reprogramming in mantle cell lymphoma promotes BTK inhibitor resistance

Project description:Resistance to Bruton’s tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. We demonstrate BRG1-mediated chromatin remodeling as a major driver of BTKi resistance. We show that cancer-associated BRG1 ATPase domain mutations protect cells from BTKi-induced ferroptosis by limiting reactive oxygen species (ROS) production and labile iron. Mechanistically, the BRG1T910M mutation activates the unfolded protein response (UPR) via ATF4, leading to upregulation of MEF2B, a key suppressor of ferroptosis. MEF2B further inhibits mitochondrial respiration and thus prevent BTKi-induced mitophagy and ferroptosis. Pharmacological inhibition of BRG1 promotes ferroptosis by suppressing pro-survival B cell receptor (BCR) signaling and the ATF4-MEF2B axis. We show that a clinical stage BRG1 inhibitor restores ferroptosis in BTKi-resistant cells and synergizes with BTKi across various MCL models. Together we propose for co-targeting BRG1 and BTK in treatment of B-cell malignancies.

2025-09-01 | GSE305144 | GEO

Ironomycin induces Mantle Cell Lymphoma cell death by targeting iron metabolism adicction

Project description:Mantle Cell lymphoma (MCL) remains an aggressive and incurable cancer with existing therapies, presenting a significant unmet clinical need. We evaluated the therapeutic interest of targeting iron homeostasis with Ironomycin alone and combined with ibrutinib, a BTK inhibitor accepted for the treatment of MCL patients. Patients commonly develop resistance to ibrutinib treatment. We found that ironomycin synergizes with ibrutinib to kill MCL cells even in ibrutinib-resistant cell lines.

2025-03-19 | GSE273121 | 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

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

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

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 NFκB target genes including Bruton’s 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.

2015-12-31 | GSE70651 | GEO

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

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