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Direct in vivo evidence for B-cell receptor and NF-KB activation in mantle cell lymphoma: role of the lymph node microenvironment and activating mutations. [RNA-Seq]

ABSTRACT: We provide direct in vivo evidence for activation of the BCR and canonical NF-KB pathways in MCL that, in the absence of activating mutations, is dependent on the lymph node microenvironment. This finding provides a mechanistic explanation for the surprising efficacy of ibrutinib for the treatment of this type of lymphoma. Mutations in components of the BCR and NF-KB pathways are associated with cell-autonomous signaling and resistance to ibrutinib. Lymph node biopsies and peripheral blood samples were obtained from patients with previously untreated MCL.

ORGANISM(S): Homo sapiens

SUBMITTER: Delong Liu

PROVIDER: E-GEOD-70926 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma.

Saba Nakhle S NS Liu Delong D Herman Sarah E M SE Underbayev Chingiz C Tian Xin X Behrend David D Weniger Marc A MA Skarzynski Martin M Gyamfi Jennifer J Fontan Lorena L Melnick Ari A Grant Cliona C Roschewski Mark M Navarro Alba A Beà Sílvia S Pittaluga Stefania S Dunleavy Kieron K Wilson Wyndham H WH Wiestner Adrian A

Blood 20160428 1

To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signali ...[more]

PMID: 27127301

Similar Datasets

Direct in vivo evidence for B-cell receptor and NF-KB activation in mantle cell lymphoma: role of the lymph node microenvironment and activating mutations. [Affymetrix]

Project description:We provide direct in vivo evidence for activation of the BCR and canonical NF-KB pathways in MCL that, in the absence of activating mutations, is dependent on the lymph node microenvironment. This finding provides a mechanistic explanation for the surprising efficacy of ibrutinib for the treatment of this type of lymphoma. Mutations in components of the BCR and NF-KB pathways are associated with cell-autonomous signaling and resistance to ibrutinib. Lymph node biopsies and peripheral blood samples were obtained from 55 patients with previously untreated MCL. The samples are distributed into 3 groups: peripheral blood (purified CD19, N=17), unpurified lymph node biopsy (mixed tissue biopsy, N=34), and purified lymph node (purified CD19 Tumor, N=4).

2016-07-15 | E-GEOD-70910 | biostudies-arrayexpress

Direct in vivo evidence for B-cell receptor and NF-KB activation in mantle cell lymphoma: role of the lymph node microenvironment and activating mutations. [RNA-Seq]

2016-07-15 | GSE70926 | GEO

Direct in vivo evidence for B-cell receptor and NF-KB activation in mantle cell lymphoma: role of the lymph node microenvironment and activating mutations. [Affymetrix]

2016-07-15 | GSE70910 | GEO

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

ABPP of Ibrutinib Resistance in B Cell Malignancies

Project description:Ibrutinib,a novel Bruton'styrosine kinase inhibitor, demonstrated high response rates in B-cell lymphomas but a growing number of ibrutinib treated patients relapse with resistance, fulminant progression and accelerated mortality. Using chemical proteomics and a high-throughput ex vivo assay in a reconstructed tumor microenvironment (TME), we determined the molecular basis for ibrutinib activity and mechanism of acquired ibrutinib resistance. Reciprocal activation of PI3K-AKT-mTOR and integrin β1 signaling were identified as a signaling hub of kinome for ibrutinib resistance, resulting in enforced TME-lymphoma interactions, promoting mantle cell lymphoma (MCL) growth and drug resistance. Combinatorial disruption of BCR signaling and ibrutinib resistance associated pathways led to release of MCL cells from TME, reversal of drugresistance and enhanced anti-MCL activity in murine and patient-derived xenograft models. This study integrated TME-mediated de-novo and acquired drug resistance mechanisms and provides the rationale for novel combination therapeutic strategy against MCL and other B cell malignancies.

2018-10-26 | PXD005734 | Pride

Direct in vivo evidence for B-cell receptor and NF-KB activation in mantle cell lymphoma: role of the lymph node microenvironment and activating mutations.

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-15 | E-GEOD-70927 | biostudies-arrayexpress

Divergent Mechanisms of Oncogenic B Cell Receptor Signaling in Lymphoma

Project description:B cell receptor (BCR) signaling has emerged as a therapeutic target in B cell lymphomas, but the precise deployment of inhibitors to target oncogenic BCR signaling requires detailed knowledge of the signaling cascades that the BCR triggers in individual tumors. Here, we have used CRISPR-Cas9 screens to investigate whether the ABC and GCB molecular subtypes of diffuse large B cell lymphoma (DLBCL) utilize distinct BCR signaling modes to sustain their proliferation and survival. Constitutive germinal center (GC) BCR signaling in GCB DLBCLs requires the BCR, CD19 and SYK engaging PI(3) kinase for survival. In ABC DLBCLs with oncogenic mutations in the BCR and MYD88, a novel BCR-TLR9-MYD88 signaling supercomplex is assembled on endolysosomal membranes that engages NF-kB. Our data explain why this subset of ABC DLBCL tumors respond frequently to ibrutinib, an inhibitor of BCR-dependent NF- kB activation, while GCB DLBCLs are insensitive, and thus provide a roadmap for the rational development of BCR pathway inhibitors in molecular subtypes of DLBCL.

2018-05-01 | GSE99276 | GEO

Targeting N-linked Glycosylation for the Therapy 1 of Aggressive Lymphomas

Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with two major biological subtypes, activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors promotes their clustering in the plasma membrane, thereby initiating chronic active signaling and downstream activation of the pro-survival NF-kB and PI3 kinase pathways. The potential of therapeutics targeting chronic active BCR signaling in ABC DLBCL is highlighted by the frequent response of these tumors to inhibitors of BTK, a kinase that links BCR signaling to NF-kB activation. Here we used genome-wide CRISPR-Cas9 screens to identify regulators of the IRF4, a direct NF-kB target and essential transcription factor in ABC cells. Unexpectedly, inactivation of the oligosaccharyltransferase (OST) complex, which mediates N-linked protein glycosylation, reduced IRF4 expression and NF-kB activity in ABC cells, resulting in cell death. Using functional glycoproteogenomics we linked this phenomenon to defective BCR glycosylation. Pharmacologic inhibition of OST reduced the size and abundance of BCR microclusters in the plasma membrane and blocked their internalization. These reorganized BCRs associated with the inhibitory coreceptor CD22, which attenuated proximal BCR signaling, thereby reducing NF-kB and PI3 kinase activation. OST inhibition also blocked the trafficking of TLR9 to the endolysosomal compartment, preventing its association with the BCR in the My-T-BCR signaling complex that activates NF-kB in ABC cells. In GCB DLBCL, OST inhibition also attenuated constitutive BCR signaling, reducing PI3 kinase signaling and triggering cell death. Our data highlight the therapeutic potential of OST inhibitors for the treatment of diverse B cell malignancies in which constitutive BCR signaling is essential.

2023-04-24 | PXD038951 | Pride

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

B-cell receptor driven MALT1 activity regulates MYC signaling in mantle cell lymphoma

Project description:Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by poor clinical outcome. Recent studies revealed the importance of BCR signaling in maintaining MCL survival. However, it remains unclear which role MALT1, an essential component of the CARD11-BCL10-MALT1 (CBM) complex that transfers BCR signaling to the NF-kB pathway, plays in the biology of MCL. Here we show that a subset of MCLs is addicted to MALT1, as its inhibition by either RNA or pharmacologic interference induced cytotoxicity both in vitro and in vivo. Gene expression profiling following MALT1 inhibition demonstrated that MALT1 controls a MYC-driven gene expression network predominantly through increased MYC protein stability. Thus our analyses identify a previously unappreciated regulatory mechanism of MYC expression. Investigating primary mouse splenocytes, we could demonstrate that MALT1 induced MYC regulation is not restricted to MCL, but represents a common mechanism of MYC regulation. MYC itself is pivotal for MCL survival as its downregulation and pharmacologic inhibition induced cytotoxicity in all MCL models. Collectively, these results provide a strong mechanistic rationale to investigate the therapeutic efficacy in targeting the MALT1-MYC axis in MCL patients.

2017-02-24 | GSE81552 | GEO

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