Bifurcated BACH2 control coordinates mantle cell lymphoma survival and dispersal during hypoxia.
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ABSTRACT:
SUBMITTER: Zhang H
PROVIDER: S-EPMC5553575 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-κB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-κB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the current study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-κB/IL6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-κB and IL6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy. Cancer Res; 76(21); 6410-23. ©2016 AACR.
| S-EPMC5093039 | biostudies-literature
Project description:BackgroundBortezomib (BTZ) is an inhibitor of the proteasome that has been used to treat patients with mantle cell lymphoma (MCL), but the resistance to BTZ in clinical cases remains a major drawback. BACH2 is a lymphoid-specific transcription repressor recognized as a tumor suppressor in MCL. Reduced BACH2 levels contribute to BTZ resistance; however, the molecular events underlying BACH2-mediated BTZ resistance are largely unclear.MethodsWe silenced BACH2 in MCL cells using a lentiviral shRNA-mediated knockdown system. Bioinformatic, real-time RT-PCR, immunoblotting and a series of functional assays were performed to describe the molecular mechanisms underlying BTZ resistance in MCL. The therapeutic effects of chemicals were evaluated on numerous cellular and molecular processes in resistant MCL cell lines and xenografts.ResultsIn resistant cells, BTZ-triggered mild oxidative stress induced a strong activation of PI3K-AKT signaling, which further blocked nuclear translocation of BACH2. Defective nuclear translocation of BACH2 or silencing BACH2 removed its transcriptional repression on HMOX1, leading to upregulation of heme oxygenase-1 (HO-1). Increased HO-1 further maintained reactive oxygen species (ROS) within a minimal tumor-promoting level and enhanced cytoprotective autophagy. Interestingly, although mild increase in ROS exhibited a pro-tumorigenic effect on resistant cells, simply blocking ROS by antioxidants did not lead to cell death but aggravated BTZ resistance via stabilizing BACH1, the other member of BACH family. Instead, 3-methyladenine (3-MA), a dual inhibitor to suppress PI3K signaling and autophagosome formation, sensitized resistant MCL cells to BTZ, both in vitro and in vivo.ConclusionOur results dissected the interconnected molecular network in resistant MCL cells in which 3-MA represents an effective therapeutic strategy to overcome BTZ resistance. Notably, BACH1 and BACH2, albeit from the same family, are likely to play opposite roles in pathogenesis and progression of MCL.
| S-EPMC8157467 | biostudies-literature
Project description:BACH2, a B-cell specific transcription factor, plays a critical role in oxidative stress-mediated apoptosis. Bortezomib (Velcade(TM)) is widely used to treat relapsed mantle cell lymphoma (MCL) patients despite varying clinical outcomes. As one of the potential mechanisms of action, bortezomib was reported to elicit endoplasmic reticulum (ER) stress which triggers reactive oxygen species (ROS). In the present study, we investigated the redox-sensitive intracellular mechanism that might play a critical role in bortezomib response in MCL cells. We demonstrated that in MCL cells that are sensitive to bortezomib treatments, BACH2 was translocated to the nucleus in response to bortezomib and induced apoptotic responses through the modulation of anti-oxidative and anti-apoptotic genes. On the other hand, in bortezomib resistant cells, BACH2 expression was confined in the cytoplasm and no suppression of antiapoptotic or antioxidative genes, Nrf2, Gss, CAT, HO-1 and MCL1, was detected. Importantly, levels of BACH2 were significantly higher in bortezomib sensitive MCL patient cells, indicating that BACH2 levels could be an indicator for clinical bortezomib responses. BACH2 translocation to the cytoplasm after phosphorylation was inhibited by PI3K inhibitors and combinatory regimens of bortezomib and PI3K inhibitors sensitized MCL cells to bortezomib. These data suggest that cellular distribution of BACH2 in response to ROS determines the threshold for the induction of apoptosis. Therapies that inhibit BACH2 phosphorylation could be the key for increasing bortezomib cytotoxic response in patients.
| S-EPMC3732253 | biostudies-literature
Project description:TGF-?-activated kinase 1 (TAK1), a member of the MAPK kinase family, plays a key role in B-cell growth and development. In the present study, we examined the potential role of TAK1 as a therapeutic target for lymphoma. Here, we show that the active phosphorylated form of TAK1 is abundantly expressed in a panel of lymphoma cell lines, including mantle cell, anaplastic large cell, and Hodgkin lymphoma cell lines. Silencing TAK1 expression via the use of siRNA inhibited the activation of NF-?B and p38 and induced apoptosis in lymphoma cell lines. Moreover, submicromolar concentrations of AZ-TAK1, a novel ATP-competitive small molecule inhibitor of TAK1, dephosphorylated TAK1, p38, and I?B-? in lymphoma cell lines. These molecular events were associated with the release of cytochrome c into the cytosol, down-regulation of X-linked inhibitor of apoptosis, activation of caspase 9, and induction of apoptosis. We also demonstrate that primary lymphoma cells express TAK1 and pTAK1 and were sensitive to AZ-TAK1-mediated cell death. Collectively, our data demonstrate an essential role for TAK1 in regulating critical survival mechanisms in lymphoma and suggest that it may serve as a therapeutic target.
| S-EPMC3460632 | biostudies-literature
Project description:Exosome complex (EXOSC) genes, which encode a multi-protein intracellular complex, mediate the degradation of various types of RNA molecules. EXOSCs, also known as polymyositis/scleroderma complexes, exist in eukaryotic cells and archaea, and primarily mediate 3' to 5'mRNA degradation. However, how EXOSC genes are implicated in processes of B-cell immune-associated pathways and B-cell tumorigenesis remains unclear. The present bioinformatics study indicated that 6 of 10 EXOSC genes, particularly the EXO.index, were able to predict the survival of patients with mantle cell lymphoma (MCL), by analyzing gene expression profiles of 123 patients with MCL from the Gene Expression Omnibus database. The results suggested that EXOSC gene expression may be a molecular marker for MCL. Compared with the whole transcript profile, patients with MCL with a high EXO.index exhibited poorer survival and decreased RNA levels, which was also verified in a second dataset. The EXOSC genes may be associated with DNA repair and B-cell activation pathways, which may be the cause of poorer survival of patients with MCL.
| S-EPMC6781731 | biostudies-literature
Project description:Because there have been a dvances in frontline treatment for mantle cell lymphoma (MCL) over the last 2 decades, we sought to characterize the changes in frontline treatment patterns and their association with outcomes. Patients with newly diagnosed MCL from September 2002 through June 2015 were enrolled in a prospective cohort study, and clinical characteristics, treatment, and clinical outcomes were compared between patients diagnosed from 2002 to 2009 (Era 1) compared with 2010 to 2015 (Era 2). Patient age, sex, and simplified MCL International Prognostic Index (sMIPI) score were similar between the 2 groups. In patients age 65 years or younger, there was less use of rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-Hyper-CVAD) (16.1% vs 8.8%) but more use of rituximab plus maximum-strength cyclophosphamide, doxorubicin, vincristine, and prednisone (R-maxi-CHOP) alternating with rituximab plus high-dose cytarabine (R-HiDAC), also known as the Nordic regimen, and R-CHOP alternating with rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) (1.1% vs 26.4%) and less use of R-CHOP or R-CHOP-like regimens (64.5% vs 35.2%) but more use of R-bendamustine (0% vs 12.1%) in Era 2 (P < .001). These changes were associated with improved event-free survival (EFS; 5-year EFS, 34.3% vs 50.0%; P = .010) and overall survival (OS; 5-year OS, 68.8% vs 81.6%; P = .017) in Era 2. In patients older than age 65 years, there was less use of R-CHOP or R-CHOP-like therapy (39.0% vs 14.3%) and nonstandard systemic therapy (36.6% vs 13.0%) but more use of R-bendamustine (0% vs 49.4%). These changes were associated with a trend for improved EFS (5-year EFS, 25.4% vs 37.5%; P = .051) in Era 2. The shift from R-CHOP or R-CHOP-like regimens to R-bendamustine was associated with improved EFS (5-year EFS, 25.0% vs 44.6%; P = .008) in Era 2. Results from this prospective cohort study provide critical real-world evidence for improved outcomes with evolving frontline patterns of care in patients with MCL.
| S-EPMC8864651 | biostudies-literature
Project description:PURPOSE:Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS:We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed. RESULTS:Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION:In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.
| S-EPMC7554677 | biostudies-literature
Project description:BackgroundMantle cell lymphoma (MCL) is widely considered an incurable malignancy even with current therapies and relapsed/refractory (R/R) disease to primary treatment remains common. With improved treatment guidelines and the advent of novel agents, patients are increasingly being treated with more lines of regimens. However, outcomes after each line of treatment remain poorly characterized, especially in the Asian population. In this paper, we described the survival outcomes in a group of R/R MCL patients.MethodsWe retrospectively studied 35 patients with R/R MCL between 1998 and 2020 at the National Cancer Centre Singapore. Patients were followed longitudinally throughout their disease course. Overall survival (OS) and progression-free survival (PFS) were determined by the Kaplan-Meier method.ResultsThe median OS and PFS from diagnosis were 105 and 40 months, respectively. After first relapse, the median OS and PFS were 52 and 19 months, post-second relapse 32 and 8 months, and post-third relapse 12 and 6 months, respectively. Patients older than 65 years at first relapse had shorter survival (median OS: 22 vs. 55 months, P = 0.0417; median PFS: 9 vs. 29 months, P = 0.001). Early treatment failure after first line therapy was also associated with worse survival outcomes (median OS: 13 vs. 55 months, P < 0.001; median PFS: 9 vs. 26 months, P < 0.001).ConclusionWith each relapse, survival outcomes for patients with MCL are worse. Novel treatment and contemporary outcomes of R/R MCL are encouraging and support the need for continued research in this area.
| S-EPMC8425802 | biostudies-literature
Project description:While classical nodal mantle cell lymphoma (cMCL) is often associated with involvement of multiple extranodal sites, isolated extranodal disease (ED) at the time of diagnosis is a rare event; data on the outcome of these forms are lacking. On behalf of the European MCL Network, we conducted a retrospective analysis on the clinical characteristics and outcomes of MCL presenting with isolated or predominant ED (MALT MCL). We collected data on 127 patients with MALT MCL diagnosed from 1998 to 2015: 78 patients (61%) were male with a median age of 65 years. The involved sites include: upper airways + Waldeyer ring (40; 32%), gastrointestinal tract (32; 25%), ocular adnexa (17; 13%), oral cavity and salivary glands (17; 13%) and others (13; 1%); 7 patients showed multiple extranodal sites. The median follow-up was 80 months (range: 6-182), 5-year progression-free survival (PFS) was 45% (95% CI: 35-54) and 5-year overall survival (OS) was 71% (95% CI: 62-79). In an explorative setting, we compared MALT MCL with a group of 128 cMCL patients: MALT MCL patients showed a significantly longer PFS and OS compared with nodal cMCL; with a median PFS of 4.5 years vs 2.8 years (p?=?0.001) and median OS of 9.8 years vs 6.9 years (p?=?0.018), respectively. Patients with MALT MCL at diagnosis showed a more favorable prognosis and indolent course than classical nodal type. This clinical variant of MCL should be acknowledged to avoid possible over-treatment.
| S-EPMC7000480 | biostudies-literature
Project description:Gene expression analyis of primary MCL including IGHV mutated and unmutated cases Gene set analysis was perfomed in MCL samples, comparing IGHV mutated cases vs. IGHV unmutated cases
2013-06-25 | GSE36000 | GEO