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SMARCA2 Deficiency Drives BTK Inhibitor Resistance in Mantle Cell Lymphoma by Metabolic Reprogramming via Epigenetic TENT5C Silencing [RNA-seq knockdown]

ABSTRACT: Mantle cell lymphoma (MCL) remains incurable, and resistance to Bruton's tyrosine kinase inhibitors (BTKis) limits long-term outcomes. Here, we identified SMARCA2 deletion or low expression as a driver of BTKi resistance and poor survival in MCL. SMARCA2 loss promoted proliferation and resistance by activating oxidative phosphorylation (OXPHOS) and suppressing reactive oxygen species. Integrative transcriptomic and epigenomic analyses identified TENT5C as a direct SMARCA2 target. SMARCA2 deficiency increased H3K27me3 at the TENT5C locus, reducing chromatin accessibility and silencing its expression. Restoring TENT5C reversed OXPHOS activation and ibrutinib resistance. Mechanistically, TENT5C interacted with ATP5A1, and upregulated its inhibitor IF1 to suppress ATP synthase activity. The flavonoid Isoginkgetin synergized with ibrutinib by inhibiting both OXPHOS and BCR signaling in preclinical models. Our findings reveal a SMARCA2-TENT5C-ATP axis linking chromatin remodeling to mitochondrial metabolism, offering novel biomarkers and therapeutic strategies for relapsed/refractory MCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE326347 | GEO | 2026/09/23

REPOSITORIES: GEO

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SMARCA2 Deficiency Drives BTK Inhibitor Resistance in Mantle Cell Lymphoma by Metabolic Reprogramming via Epigenetic TENT5C Silencing

Project description:Mantle cell lymphoma (MCL) remains incurable, and resistance to Bruton's tyrosine kinase inhibitors (BTKis) limits long-term outcomes. Here, we identified SMARCA2 deletion or low expression as a driver of BTKi resistance and poor survival in MCL. SMARCA2 loss promoted proliferation and resistance by activating oxidative phosphorylation (OXPHOS) and suppressing reactive oxygen species. Integrative transcriptomic and epigenomic analyses identified TENT5C as a direct SMARCA2 target. SMARCA2 deficiency increased H3K27me3 at the TENT5C locus, reducing chromatin accessibility and silencing its expression. Restoring TENT5C reversed OXPHOS activation and ibrutinib resistance. Mechanistically, TENT5C interacted with ATP5A1, and upregulated its inhibitor IF1 to suppress ATP synthase activity. The flavonoid Isoginkgetin synergized with ibrutinib by inhibiting both OXPHOS and BCR signaling in preclinical models. Our findings reveal a SMARCA2-TENT5C-ATP axis linking chromatin remodeling to mitochondrial metabolism, offering novel biomarkers and therapeutic strategies for relapsed/refractory MCL.

2026-09-23 | GSE326345 | GEO

SMARCA2 Deficiency Drives BTK Inhibitor Resistance in Mantle Cell Lymphoma by Metabolic Reprogramming via Epigenetic TENT5C Silencing [RNA-seq IGK]

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Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma

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2018-10-26 | PXD005734 | Pride

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Project description:We established two representative ABC DLBCL cell lines (TMD8 and OCI-Ly10) with ibrutinib resistance by gradually increasing the concentration of ibrutinib during passage in culture. RNA-seq analysis demonstrated that the BCR pathway gene signature is enriched in resistant cell lines when compared to parental cells. The most upregulated gene is EGR1, a transcription factor that activates multiple oncogenic pathways including MYC and E2F. Elevated EGR1 expression is also observed in ibrutinib-resistant primary mantle cell lymphoma cells when treated with ibrutinib. Using multiple metabolic and genetic approaches, we discovered that overexpression of EGR1 causes metabolic reprogramming to oxidative phosphorylation (OXPHOS) and ibrutinib resistance. Mechanistically, EGR1 mediates metabolic reprogramming through transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation accelerates intracellular ATP production via the mitochondrial tricarboxylic acid (TCA) cycle, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in patient-derived xenograft mouse models.

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XPO1 inhibition antagonizes MCL via nuclear retention of IkB: Selinexor demonstrates antitumor activities in both ibr-sensitive and ibr-resistant tumor cells

Project description:Inhibition of BCR signaling through BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one-third of the patients do not respond well to the drug and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader anti-tumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell cycle arrest and XPO-1 knockdown also retarded cell growth. Further, down-regulation of the NF-B gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NF-B was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IB that was accompanied by the reduction of DNA binding activity of NF-B suggesting that NF-B is trapped in an inhibitory complex. Co-immunoprecipitation confirmed that p65 of NF-B and IB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NF-B pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NF-B inhibition.

2018-07-10 | GSE116810 | 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

Activity of the novel BTK inhibitor TG-1701 is associated with the disruption of the Ikaros signaling pathway in responder B-NHL patients and with sensitization to anti-CD20 therapy in B-NHL xenografts

Project description:Covalent Bruton's tyrosine kinase inhibitors (BTKis) have transformed the treatment of B-cell non-Hodgkin lymphoma (B-NHL), including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but their activity has been limited by off-target toxicity and acquired drug resistance. TG-1701 is a novel irreversible and highly specific BTKi being presently under study in a phase 1 clinical trial in patients with relapsed/refractory B-NHL alone and in combination with ublituximab, a CD20 antibody, and umbralisib, a dual PI3Kδ and CK1ε inhibitor. Here we show, for the first time that phosphoproteomic analysis of CLL patients receiving a BTKi (TG-1701) led to a non-supervised clustering that matched the clinical outcomes and separated a group of “responders” from a group of “non-responders”. This clustering was based on a selected list of 96 phosphosites, with Ikaros-Ser442/445 phosphorylation as a potential marker for TG-1701 efficacy. RNA-seq analysis followed by qPCR and western blot validation further revealed that TG-1701 treatment blunted the Ikaros gene signature only in responder patients, as well as in BTKi-sensitive, but not BTKi-insensitive, B-NHL cell lines and xenografts. Importantly, and in contrast with ibrutinib, TG-1701 did not impair FcγR-driven antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) triggered by the anti-CD20 antibodies rituximab and ublituximab in a multicellular MCL co-culture system. In addition, TG-1701 cooperated with ublituximab coupled to umbralisib (also referred as the U2 regimen) in reducing the tumor growth in both ibrutinib-sensitive and ibrutinib-insensitive mouse models of MCL. Altogether, these data validate phosphoproteomic as a broken thread to omics analysis in the clinic and support the use of TG-1701-U2 combination in R/R B-NHL patients, irrespective of prior response to ibrutinib.

2021-09-22 | PXD023231 | Pride

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