MCIR1: A Patient‐Derived Mantle Cell Lymphoma Line for Discovering New Treatments for Ibrutinib Resistance

2021 ◽  
Author(s):  
Xiaosheng Wu ◽  
Kevin E. Nowakowski ◽  
Jithma P. Abeykoon ◽  
Michelle Manske ◽  
Mary J. Stenson ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Lymphoma Line ◽  
Ibrutinib Resistance ◽  
New Treatments

Abstract 650: MCIR1: A patient-derived ibrutinib-resistant mantle cell lymphoma line for the study of ibrutinib resistance and drug discovery

2020 ◽  
Author(s):  
Kevin E. Nowakowski ◽  
Jithma P. Abeykoon ◽  
Mary J. Stenson ◽  
Michael M. Timm ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Lymphoma Line ◽  
Ibrutinib Resistance

scholarly journals Transcriptional programming drives Ibrutinib-resistance evolution in mantle cell lymphoma

Cell Reports ◽  
2021 ◽  
Vol 34 (11) ◽  
pp. 108870
Author(s):  
Xiaohong Zhao ◽  
Michelle Y. Wang ◽  
Huijuan Jiang ◽  
Tint Lwin ◽  
Paul M. Park ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Resistance Evolution ◽  
Mantle Cell ◽  
Ibrutinib Resistance

scholarly journals Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

2018 ◽  
Vol 2 (16) ◽  
pp. 2039-2051 ◽  
Author(s):  
Jimmy Lee ◽  
Liang Leo Zhang ◽  
Wenjun Wu ◽  
Hui Guo ◽  
Yan Li ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Resistant Cell ◽  
Intrinsic Resistance ◽  
Mantle Cell ◽  
Myc Gene ◽  
Bona Fide ◽  
Ibrutinib Resistance ◽  
Induced Apoptosis

Abstract The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.

scholarly journals HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma

Blood ◽  
2016 ◽  
Vol 128 (21) ◽  
pp. 2517-2526 ◽  
Author(s):  
Caron Jacobson ◽  
Nadja Kopp ◽  
Jacob V. Layer ◽  
Robert A. Redd ◽  
Sebastian Tschuri ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Key Points ◽  
Mantle Cell ◽  
Ibrutinib Resistance

Key Points Inhibition of HSP90 targets multiple dependences in mantle cell lymphoma. Clinically available HSP90 inhibitors overcome ibrutinib resistance in vitro and in vivo.

Iron Chelation in Mantle Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1395-1395
Author(s):  
Heather M. Gilbert ◽  
Josef T. Prchal ◽  
Miles C. Deneris
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Iron Chelation ◽  
B Cell Lymphoma ◽  
Iron Chelators ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Lymphoma Line ◽  
Large B Cell

Abstract Cell proliferation is dependent upon iron, and numerous studies have shown that iron limitation arrests cells in the G1 phase of the cell cycle. A recent study of the molecular basis of these observations (Richardson, et al. Blood2007;109:4045) examined the ability of iron chelators to inhibit cell proliferation and to induce apoptosis, focusing on the role of iron chelation on cyclin D1. Cyclin D1 assembles with cdk-4 or cdk-6, generating an active holo-enzyme that catalyzes a rate limiting step in G1/S progression. This complex phosphorylates substrates, including the retinoblastoma protein, which regulate S phase entrance. Richardson’s group demonstrated that the G1/S arrest after Fe depletion is mediated, in part, by a decrease in cyclin D1 via ubiquitin-independent proteasomal degradation. Studies looking specifically at mantle cell lymphoma cell lines, however, have not yet been reported. Mantle Cell lymphoma is an interesting target for potential iron chelation as it is associated with a balanced translocation (t11;14) which leads to upregulation of BCL1 and to the constitutive overproduction of cyclin D1. We studied five different cell lines - JeKo (Mantle Cell Lymphoma), BL-41 (Burkitt Cell Lymphoma), DG-75 (Burkitt Cell Lymphoma), SUDHL-6 (Diffuse Large B cell Lymphoma) and EBV-immortalized lymphocytes from normal controls - and incubated them with four different iron chelators - deferoxamine (DFO), 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), Pyridoxal Isonicotinoyl Hydrazone (PIH), and Salicylaldehyde Isocotinoyl Hydrazone (SIH). We then measured and compared cell cycle proliferation (using the Cellometer Auto T4, an instrument that measures cell count, cell viability, and cell size) and the rate of apoptosis (via propidium iodide FACS analysis). At 24 hours incubation, the mantle cell lymphoma lines showed significantly increased rates of apoptosis compared with non-chelated mantle cell controls (5% vs. 48%, p=0.04). The diffuse large B cell lymphoma line showed a lesser increase in apoptosis that did not reach statistical significant (6.5% vs. 14%, p=0.07), while the Burkitt’s lymphoma lines and the EBV immortalized lymphocytes showed no significant difference (BL-41, 3.4% vs. 4.1%, p=0.50; DG-75, 6% vs. 5.9%, p=0.99; EBV lymphocytes, 12.5% vs. 12.7%, p=0.96). At 72 hours of incubation with chelators, the EBV lymphocytes showed increased apoptosis compared to untreated controls (2.5% vs. 44.5%, p=0.002), while the apoptotic rate increased in the diffuse large B cell lymphoma line (3.8% vs. 48%, p=0.001) and even more dramatically in the mantle cell lymphoma line (1.5% vs. 64%, p=0.0006). The two Burkitt’s lymphoma lines were affected to a lesser degree at 72 hours by the presence of iron chelators (BL-41, 0.9% vs, 3.9%, p=0.02; DG-75, 5.5% vs. 8.9%, p=0.11). Although iron chelation, especially at longer incubation times, did affect all cell lines to various degrees, the chelator-mediated effects do appear to be specific for cell type, with mantle cell lymphoma cells displaying higher rates of apoptosis compared with other lymphomas and normal lymphocytes. These initial results will now be followed by examination of cyclin D1 expression after iron chelation. If overexpression of cyclin D1 in mantle cell lymphoma releases cells from their normal controls and acts as an oncogene, then a decrease in cyclin D1 levels via iron chelation could be added to the therapeutic armamentarium of mantle cell lymphoma.

Correlation of PI3K upregulation with NOTCH2 mutations in ibrutinib-resistant mantle cell lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20065-e20065
Author(s):  
Krystle Nomie ◽  
Preetesh Jain ◽  
Nikita Kotlov ◽  
Vitaly Segodin ◽  
Qingsong Cai ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Pi3k Pathway ◽  
Clinical Samples ◽  
Pi3k Signaling ◽  
Pi3k Inhibitors ◽  
Mantle Cell ◽  
Ibrutinib Resistance

e20065 Background: PI3K dysregulation has been linked to ibrutinib resistance in mantle cell lymphoma (MCL); however, the investigation of PI3K signaling as an important ibrutinib resistance mechanism has been rarely assessed in clinical samples. Therefore, we sought to more fully characterize PI3K dysregulation in ibrutinib-sensitive and -resistant MCL clinical samples at the genomic and transcriptomic levels. Methods: Whole exome sequencing (WES; n = 41) and RNA-seq (n = 93) were performed on fresh peripheral blood, apheresis, or biopsy patient primary samples. All analysis was performed using the BostonGene automated pipeline. Results: To evaluate ibrutinib resistance in MCL, we compared the activity of 11 cellular pathways calculated by PROGENy between ibrutinib-sensitive and -resistant MCL. The PI3K pathway was the most differentially expressed between the two groups (q < 0.005; > 1 median absolute deviation in ibrutinib-resistant MCL). Increased PI3K pathway expression in the ibrutinib-resistant MCL tumors strongly correlated with hyperproliferation (r = 0.49; p = 6e-07). Both hyperproliferation and enriched PI3K expression associated with more frequent NOTCH2 somatic mutations (~22% ibrutinib-resistant MCL with high PI3K expression (p = 0.004) and hyperproliferation (p = 0.003)) that generate a premature stop codon in the PEST domain, likely resulting in hyperactive NOTCH2. Frequent TP53 mutations were identified in ibrutinib-resistant MCL tumors (58%; 3-fold greater vs ibrutinib-sensitive tumors; p = 0.02) based on our cohort and the Agarwal et al., 2019, Nature Medicine cohort. PI3K signaling is a known p53 activator, which may lead to a compensatory tumor suppressive mechanism, indicating that PI3K activation may induce mutational pressure on TP53 to promote MCL survival. VH gene usage variability of the B-cell receptor (BCR), the inducer of PI3K signaling, was not different between ibrutinib-sensitive and -resistant MCL, suggesting that diverse BCR expression does not underlie enriched ibrutinib-resistant MCL PI3K expression. Conclusions: PI3K inhibitors have resulted in underwhelming MCL clinical outcomes; yet, the advent of next-generation PI3K inhibitors such as copanlisib with potentially greater efficacy and less toxicity warrants the continued investigation of PI3K signaling in ibrutinib-resistant MCL. We identified a strong correlation between gain-of-function NOTCH2 mutations and enriched PI3K signaling, suggesting that dual inhibition of NOTCH and PI3K may overcome ibrutinib resistance in MCL.

XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB

2018 ◽  
Vol 17 (12) ◽  
pp. 2564-2574 ◽  
Author(s):  
Mei Ming ◽  
Wenjun Wu ◽  
Bingqing Xie ◽  
Madina Sukhanova ◽  
Weige Wang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Nuclear Retention ◽  
Mantle Cell ◽  
Ibrutinib Resistance

Targeting Oxphos Pathway Against Ibrutinib Resistance to Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 290-290 ◽  
Author(s):  
Yang Liu ◽  
Taylor Bell ◽  
Hui Zhang ◽  
Yuting Sun ◽  
Carrie J Li ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Pdx Model ◽  
Mantle Cell ◽  
Ibrutinib Resistance

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is initially responsive but ultimately relapses to frontline therapy. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase (BTK) has achieved 68% of overall response rate in relapsed/refractory mantle cell lymphoma (MCL) patients. However, the vast majority of MCL patients experience disease progression, demonstrating that standard-of-care approaches are failing and that a means for targeting ibrutinib resistant MCL is clinically needed. Our hypothesis is that the ibrutinib-resistant MCL may rely on the mitochondrial oxidative phosphorylation (OXPHOS) pathway to produce energy for tumor growth. In this study, we investigated the effects of IACS-010759, a small molecule mitochondrial complex I inhibitor discovered in MD Anderson Cancer Center which can block the OXPHOS pathway, to overcome ibrutinib resistance in MCL in vitro and in a patient-derived xenograft (PDX) model. Methods: The OXPHOS metabolic pathways were investigated by RNASeq in a panel of ibrutinib-sensitive and -resistant MCL samples. Cell growth inhibition assays were tested after 72-hour treatment with IACS-010759 in ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, and ibrutinib-sensitive MCL cell lines, Rec-1, Mino, and Jeko-1, by CellTiter-Glo luminescent cell viability assay (Promega). Furthermore, an IBN-resistant MCL PDX model was established and the therapeutic effects and tolerability of IACS-010759 were investigated in the primary MCL-bearing PDX model. Results: We have done RNA sequencing (RNASeq) in 7 primary ibrutinib-resistant and 16 ibrutinib-sensitive MCL patient samples, and analyzed the data using Gene Set Enrichment Analysis (GSEA) software. The results demonstrated that the OXPHOS pathway was activated in the primary ibrutinib-resistant MCL cells but not ibrutinib-sensitive MCL cells. Based on the RNASeq data, we selected an OXPHOS inhibitor IACS-010759 to investigate its effects on both primary ibrutinib-resistant and ibrutinib-sensitive MCL cells in vitroand in PDX mice. IACS-010759 significantly inhibited cell proliferation in ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, but not in ibrutinib-sensitive MCL cell lines, Rec-1, Mino, and Jeko-1, during a 72-hour incubation. Furthermore, the primary ibrutinib-resistant MCL PDX mice were administrated with 10 mg/kg IACS-10759 by oral gavage, for 28 days using a 5 on/2 off dosing schedule. Our data showed that IACS-010759 completely eradicated tumor growth in ibrutinib-resistant MCL PDX mice (n=5, p=0.045). All mice tolerated the treatment dose and no toxicity was found during 28 days of IACS-010759 treatment. Conclusions: The OXPHOS inhibitor IACS-010759 overcomes ibrutinib resistance both in vitro and in the PDX mouse model. The investigation of its mechanism-of-action is ongoing. IACS-010759 could have the potential for clinical use in ibrutinib-resistant relapsed/refractory MCL patients. Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Dava Oncology: Honoraria; BeiGene: Research Funding; Acerta: Consultancy, Research Funding.

scholarly journals CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma

Oncotarget ◽  
2016 ◽  
Vol 7 (45) ◽  
pp. 73558-73572 ◽  
Author(s):  
Atish Mohanty ◽  
Natalie Sandoval ◽  
Manasi Das ◽  
Raju Pillai ◽  
Lu Chen ◽  
...  
Keyword(s):  
Protein Stability ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Ibrutinib Resistance

Abstract 4391: Overcoming primary ibrutinib resistance in mantle cell lymphoma

2016 ◽  
Author(s):  
Leo Zhang ◽  
Lan Pham ◽  
Hui Zhang ◽  
Jingmeng Xie ◽  
Wenjing Tao ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Ibrutinib Resistance
Sign in / Sign up

Export Citation Format

Share Document