scholarly journals Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling

2021 ◽  
Vol 22 (19) ◽  
pp. 10637
Author(s):  
Jieun Kim ◽  
Hyun-ju Lee ◽  
Seon Kyeong Park ◽  
Jin-Hee Park ◽  
Ha-Ram Jeong ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Acetylcholinesterase Inhibitors ◽  
Mapk Signaling ◽  
Inos Mrna ◽  
Mrna Levels ◽  
Stat3 Phosphorylation ◽  
5Xfad Mice

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS- and Aβ-induced neuroinflammatory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 microglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proinflammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflammasome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroinflammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphology, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and morphology. Taken together, our findings indicate that donepezil significantly downregulates LPS- and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD.

scholarly journals Oligonol Ameliorates CCl4-Induced Liver Injury in Rats via the NF-Kappa B and MAPK Signaling Pathways

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Jeonghyeon Bak ◽  
Nam Kyung Je ◽  
Hae Young Chung ◽  
Takako Yokozawa ◽  
Sik Yoon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mapk Signaling ◽  
Hepatoprotective Activity ◽  
Inos Mrna ◽  
Mrna Levels ◽  
Hepatic Diseases ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory

Oxidative stress is thought to be a key risk factor in the development of hepatic diseases. Blocking or retarding the reactions of oxidation and the inflammatory process by antioxidants could be a promising therapeutic intervention for prevention or treatment of liver injuries. Oligonol is a low molecular weight polyphenol containing catechin-type monomers and oligomers derived from lychee fruit. In this study, we investigated the anti-inflammatory effect of oligonol on carbon tetrachloride- (CCl4-) induced acute hepatic injury in rats. Oral administration of oligonol (10 or 50 mg/kg) reduced CCl4-induced abnormalities in liver histology and serum AST and serum ALT levels. Oligonol treatment attenuated the CCl4-induced production of inflammatory mediators, including TNF-α, IL-1β, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA levels. Western blot analysis showed that oligonol suppressed proinflammatory nuclear factor-kappa B (NF-κB) p65 activation, phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) as well as Akt. Oligonol exhibited strong antioxidative activityin vitroandin vivo, and hepatoprotective activity againstt-butyl hydroperoxide-induced HepG2 cells. Taken together, oligonol showed antioxidative and anti-inflammatory effects in CCl4-intoxicated rats by inhibiting oxidative stress and NF-κB activation via blockade of the activation of upstream kinases including MAPKs and Akt.

scholarly journals The 12-HHT/BLT2/NO Axis Is Associated to the Wound Healing and Skin Condition in Different Glycaemic States

2019 ◽  
Vol 7 (4) ◽  
pp. 65
Author(s):  
Leguina-Ruzzi ◽  
Ortiz Diban ◽  
Velarde
Keyword(s):  
Nitric Oxide ◽  
Wound Healing ◽  
Tight Junction ◽  
Skin Condition ◽  
Inos Mrna ◽  
Nitric Oxide Production ◽  
Mrna Levels ◽  
Oxide Production

Type 2 diabetes affects over 340 million people worldwide. This condition can go unnoticed and undiagnosed for years, leading to a late stage where high glycaemia produces complications such as delayed wound healing. Studies have shown that 12-HHT through BLT2, accelerates keratinocyte migration and wound healing. Additionally, evidence has shown the role of nitric oxide as a pro-regenerative mediator, which is decreased in diabetes. Our main goal was to study the association between the 12-HHT/BLT2 axis and the nitric oxide production in wound healing under different glycaemia conditions. For that purpose, we used in vivo and in vitro models. Our results show that the skin from diabetic mice showed reduced BLT2 and iNOS mRNA, TEER, 12-HHT, nitrites, and tight junction levels, accompanied by higher MMP9 mRNA levels. Furthermore, a positive correlation between BLT2 mRNA and nitrites was observed. In vitro, HaCaT-BLT2 cells showed higher nitric oxide and tight junction levels, and reduced MMP9 mRNA levels, compared to mock-keratinocytes under low and high glucose condition. The wound healing capacity was associated with higher nitric oxide production and was affected by the NOS inhibition. We suggest that the BLT2 expression improves the keratinocyte response to hyperglycaemia, associated with the production of nitric oxide.

scholarly journals Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

2007 ◽  
Vol 18 (8) ◽  
pp. 2864-2872 ◽  
Author(s):  
Kelly J. Perkins ◽  
Utpal Basu ◽  
Murat T. Budak ◽  
Caroline Ketterer ◽  
Santhosh M. Baby ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Molecular Mechanisms ◽  
Neuromuscular Junctions ◽  
Protein Product ◽  
Mrna Levels ◽  
Laser Capture Microscopy ◽  
Erk Phosphorylation ◽  
Duchenne's Muscular Dystrophy

Utrophin is the autosomal homologue of dystrophin, the protein product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin expression is temporally and spatially regulated being developmentally down-regulated perinatally and enriched at neuromuscular junctions (NMJs) in adult muscle. Synaptic localization of utrophin occurs in part by heregulin-mediated extracellular signal-regulated kinase (ERK)-phosphorylation, leading to binding of GABPα/β to the N-box/EBS and activation of the major utrophin promoter-A expressed in myofibers. However, molecular mechanisms contributing to concurrent extrasynaptic silencing that must occur to achieve NMJ localization are unknown. We demonstrate that the Ets-2 repressor factor (ERF) represses extrasynaptic utrophin-A in muscle. Gel shift and chromatin immunoprecipitation studies demonstrated physical association of ERF with the utrophin-A promoter N-box/EBS site. ERF overexpression repressed utrophin-A promoter activity; conversely, small interfering RNA-mediated ERF knockdown enhanced promoter activity as well as endogenous utrophin mRNA levels in cultured muscle cells in vitro. Laser-capture microscopy of tibialis anterior NMJ and extrasynaptic transcriptomes and gene transfer studies provide spatial and direct evidence, respectively, for ERF-mediated utrophin repression in vivo. Together, these studies suggest “repressing repressors” as a potential strategy for achieving utrophin up-regulation in DMD, and they provide a model for utrophin-A regulation in muscle.

scholarly journals Novel insights into the regulation of chemerin expression: role of acute-phase cytokines and DNA methylation

2019 ◽  
Author(s):  
Kamila Kwiecien ◽  
Piotr Brzoza ◽  
Pawel Majewski ◽  
Izabella Skulimowska ◽  
Kamil Bednarczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Phase ◽  
Molecular Mechanisms ◽  
Retinoic Acid Receptor ◽  
Constitutive Expression ◽  
Sequencing Analysis ◽  
Mrna Levels ◽  
Pleiotropic Actions

AbstractChemerin is a chemoattractant protein with adipokine properties encoded by the retinoic acid receptor responder 2 (RARRES2) gene. It has gained more attention over the past few years due to its multilevel impact on metabolism and immune responses. The pleiotropic actions of chemerin include chemotaxis of dendritic cells, macrophages and natural killers (NK) subsets, bactericidal activity as well as regulation of adipogenesis and glucose metabolism. Therefore, reflecting the pleiotropic actions of chemerin, expression of RARRES2 is regulated by a variety of inflammatory and metabolic mediators. However, for most cell types, the molecular mechanisms controlling constitutive and regulated chemerin expression are poorly characterized. Here we show that RARRES2 mRNA levels in murine adipocytes are upregulated in vitro and in vivo by acute-phase cytokines, IL-1β and OSM. In contrast to adipocytes, these cytokines exerted a weak, if any, response in mouse hepatocytes, suggesting that the effect of IL-1β and OSM on chemerin expression is specific to fat tissue. Moreover, we show that DNA methylation controls the constitutive expression of chemerin. Bisulfite sequencing analysis showed low methylation levels within −735 to +258 bp of the murine RARRES2 gene promoter in unstimulated adipocytes and hepatocytes. In contrast to these cells, the RARRES2 promoter is highly methylated in B lymphocytes, cells that do not produce chemerin. Together, our findings reveal previously uncharacterized mediators and mechanisms controlling chemerin expression in various cells.

scholarly journals The selective NLRP3 inhibitor MCC950 hinders atherosclerosis development by attenuating inflammation and pyroptosis in macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wenyun Zeng ◽  
Danbin Wu ◽  
Yingxin Sun ◽  
Yanrong Suo ◽  
Qun Yu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
In Vitro Study ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
High Fat ◽  
Nlrp3 Inflammasome Activation ◽  
Atherosclerosis Development

AbstractNLRP3 inflammasome is a vital player in macrophages pyroptosis, which is a type of proinflammatory cell-death and takes part in the pathogenesis of atherosclerosis. In this study, we used apoE−/− mice and ox-LDL induced THP-1 derived macrophages to explore the mechanisms of MCC950, a selective NLRP3 inhibitor in treating atherosclerosis. For the in vivo study, MCC950 was intraperitoneal injected to 8-week-old apoE−/− mice fed with high-fat diet for 12 weeks. For the in vitro study, THP-1 derived macrophages were treated with ox-LDL and MCC950 for 48 h. MCC950 administration reduced plaque areas and macrophages contents, but did not improve the serum lipid profiles in aortic root of apoE−/− mice. MCC950 inhibited the activation of NLRP3/ASC/Caspase-1/GSDMD-N axis, and alleviated macrophages pyroptosis and the production of IL-1β and IL-18 both in aorta and in cell lysates. However, MCC950 did not affect the expression of TLR4 or the mRNA levels of NLRP3 inflammasome and its downstream proteins, suggesting that MCC950 had no effects on the priming of NLRP3 inflammasome activation in macrophages. The anti-atherosclerotic mechanisms of MCC950 on attenuating macrophages inflammation and pyroptosis involved in inhibiting the assembly and activation of NLRP3 inflammasome, rather than interrupting its priming.

scholarly journals FGF18–FGFR2 signaling triggers the activation of c-Jun–YAP1 axis to promote carcinogenesis in a subgroup of gastric cancer patients and indicates translational potential

Oncogene ◽  
2020 ◽  
Vol 39 (43) ◽  
pp. 6647-6663
Author(s):  
Jinglin Zhang ◽  
Chi Chun Wong ◽  
Kam Tong Leung ◽  
Feng Wu ◽  
Yuhang Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Nuclear Accumulation ◽  
Cancer Drug ◽  
Oncogenic Signaling ◽  
Antitumor Effects ◽  
Primary Tumors

Abstract Fibroblast growth factor receptor type 2 (FGFR2) has emerged as a key oncogenic factor that regulates gastric cancer (GC) progression, but the underlying mechanism of FGF–FGFR2 signaling pathway remains largely unknown. To identify the potential molecular mechanisms of the oncogenic FGFR2 in gastric carcinogenesis and convey a novel therapeutic strategy, we profiled the FGFR alterations and analyzed their clinical associations in TCGA and Hong Kong GC cohorts. We found that FGFR2 overexpression in GC cell lines and primary tumors predicted poor survival and was associated with advanced stages of GC. Functionally, growth abilities and cell cycle progression of GC were inhibited by inactivation of ERK–MAPK signal transduction after FGFR2 knockdown, while apoptosis was promoted. Meanwhile, the first-line anti-cancer drug sensitivity was enhanced. RNA-seq analysis further revealed that YAP1 signaling serves as a significant downstream modulator and mediates the oncogenic signaling of FGFR2. When stimulating FGFR2 by rhFGF18, we observed intensified F-actin, nuclear accumulation of YAP1, and overexpression of YAP1 targets, but these effects were attenuated by either FGFR2 depletion or AZD4547 administration. Additionally, the FGF18–FGFR2 signaling upregulated YAP1 expression through activating c-Jun, an effector of MAPK signaling. In our cohort, 28.94% of GC cases were characterized as FGFR2, c-Jun, and YAP1 co-positive and demonstrated worse clinical outcomes. Remarkably, we also found that co-targeting FGFR2 and YAP1 by AZD4547 and Verteporfin synergistically enhanced the antitumor effects in vitro and in vivo. In conclusion, we have identified the oncogenic FGF–FGFR2 regulates YAP1 signaling in GC. The findings also highlight the translational potential of FGFR2–c-Jun–YAP1 axis, which may serve as a prognostic biomarker and therapeutic target for GC.

scholarly journals Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

2020 ◽  
Author(s):  
Han Seok Koh ◽  
Hannah Jang ◽  
SooKil Tae ◽  
mi-sun Lee ◽  
Jae-Woong Min ◽  
...  
Keyword(s):  
Mouse Model ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Precentral Gyrus ◽  
Alzheimer Patient ◽  
5Xfad Mice

Abstract Background Alzheimer`s disease (AD) is a progressive neurodegenerative disease worldwide. Accumulation of amyloid-β (Aβ), neurofibrillary tangles and neuroinflammation play the important neuro-pathology in patients with AD. miRNA is multifunctional and involved in physiological and pathological processes. Recently, microRNAs have been linked to neurodegenerative diseases. However, it is little known whether miRNA dysregulation contributes to AD pathology progression such as Aβ processing, phagocytosis and neuroinflammation. Here, we identify miR485-3p as a novel modulator of AD pathology in 5XFAD mice. Methods To study the role of miR485-3p in AD, we used in control or miR485-3p antisense oligonucleotides (miR485-3p ASO) injected 5XFAD mouse model. Changes of Aβ processing and clearance and inflammation were analyzed by biochemical method in vitro and in vivo. Result This study suggests that miR485-3p, a novel miRNA targeting SIRT1 may contribute to pathogenesis in an AD mouse. We found SIRT1 is significantly reduced in the precentral gyrus of Alzheimer patient`s and in 5XFAD mice. To determine whether the inhibition of miRNA 485-3p would affect AD pathology, we studied the effect of the antisense oligo in the brain of 5XFAD mice through direct intracerebral ventricular injection with miR485-3p ASO. We demonstrated that miR485-3p ASO significantly reduced Aβ plaque and amyloid biosynthetic enzyme. Importantly, the attenuation of Aβ plaques through miR485-3p ASO was mediated through Aβ phagocytic activity of glial cells, by which it can directly target CD36. MiR485-3p ASO also decreased inflammatory responses. Collectively, these responses inhibited neuronal loss caused by Aβ lead to improvements of cognitive impairment. Conclusion Our data provide evidence for the molecular mechanisms which underlie the miR485-3p ASO responses in an AD mouse model. These results suggest that attenuating miRNA 485-3p levels might represent a novel therapeutic approach in AD.

scholarly journals KIF15 Accelerated The Progression of Nasopharyngeal Carcinoma and Predict Poor Prognosis

2021 ◽  
Author(s):  
Yongli Wang ◽  
Yong Yang ◽  
Ying Qin ◽  
Fei Liu ◽  
Jingcheng Shu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Colony Formation ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Mapk Signaling ◽  
Antibody Array ◽  
Mechanism Study ◽  
Mouse Xenograft Model

Abstract Background: Nasopharyngeal carcinoma (NPC) is a common tumor in head and neck and is prevailing in China. Although treatment methods continue to improve, the prognosis of advanced patients is still unsatisfactory. Kinesin family member 15 (KIF15) is a kind of protein, which regulates the process of cell mitosis and plays an important role in several types of human cancers. This study aims to investigate the role of KIF15 in NPC.Methods: First, the differential expression of KIF15 in NPC and para-carcinoma tissues was evaluated based on both data collected from Gene Expression Omnibus (GEO) database and immunohistochemical analysis on clinical specimens collected from in-house cohort. Next, cell lines C666-1 and CNE-2Z were selected for the construction of KIF15‑knockdown cell models. Then, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, wound healing, Transwell and clone formation assays were used to detect the proliferation, apoptosis, migration, invasion and colony formation of nasopharyngeal carcinoma cells in vitro. A mouse xenograft model was constructed for in vivo study. Furthermore, Human Apoptosis Antibody Array kit was used to screen possible targets of KIF15 in NPC. In the end, the potential molecular mechanisms underlying the effects of KIF15 was explored through western blot analysis.Results: The results showed that the expression of KIF15 in NPC tissues is higher than that in para-carcinoma tissues, and high levels of KIF15 expression are associated with low survival rates. In addition, knockdown of KIF15 inhibited cell proliferation, migration, invasion and colony formation ability, and promoted cell apoptosis. What’s more, in vivo xenograft experiments showed that down-regulation of KIF15 can inhibit NPC tumor growth. Moreover, the mechanism study demonstrated a variety of apoptosis-related proteins as well as PI3K/AKT and MAPK signaling pathways may be involved in KIF15-induced regulation of NPC.Conclusions: In short, we demonstrated that KIF15 is overexpressed and accelerated the progression of nasopharyngeal carcinoma. It can be used as a new prognostic indicator as well as a potential drug target for the treatment of NPC.

scholarly journals Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc

Bone Research ◽  
2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Sheng Chen ◽  
Xiaohao Wu ◽  
Yumei Lai ◽  
Di Chen ◽  
Xiaochun Bai ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Mechanical Stress ◽  
Nucleus Pulposus ◽  
Nlrp3 Inflammasome ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

AbstractIntervertebral disc (IVD) degeneration (IVDD) is the main cause of low back pain with major social and economic burdens; however, its underlying molecular mechanisms remain poorly defined. Here we show that the focal adhesion protein Kindlin-2 is highly expressed in the nucleus pulposus (NP), but not in the anulus fibrosus and the cartilaginous endplates, in the IVD tissues. Expression of Kindlin-2 is drastically decreased in NP cells in aged mice and severe IVDD patients. Inducible deletion of Kindlin-2 in NP cells in adult mice causes spontaneous and striking IVDD-like phenotypes in lumbar IVDs and largely accelerates progression of coccygeal IVDD in the presence of abnormal mechanical stress. Kindlin-2 loss activates Nlrp3 inflammasome and stimulates expression of IL-1β in NP cells, which in turn downregulates Kindlin-2. This vicious cycle promotes extracellular matrix (ECM) catabolism and NP cell apoptosis. Furthermore, abnormal mechanical stress reduces expression of Kindlin-2, which exacerbates Nlrp3 inflammasome activation, cell apoptosis, and ECM catabolism in NP cells caused by Kindlin-2 deficiency. In vivo blocking Nlrp3 inflammasome activation prevents IVDD progression induced by Kindlin-2 loss and abnormal mechanical stress. Of translational significance, adeno-associated virus-mediated overexpression of Kindlin-2 inhibits ECM catabolism and cell apoptosis in primary human NP cells in vitro and alleviates coccygeal IVDD progression caused by mechanical stress in rat. Collectively, we establish critical roles of Kindlin-2 in inhibiting Nlrp3 inflammasome activation and maintaining integrity of the IVD homeostasis and define a novel target for the prevention and treatment of IVDD.

Targeting BCR-Independent Proliferation of CLL Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2916-2916
Author(s):  
Slinger Erik ◽  
Arnon P. Kater ◽  
Rachel Thijssen ◽  
Eric Eldering
Keyword(s):  
Lymph Node ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Clinical Success ◽  
Development Of Resistance ◽  
Stat3 Phosphorylation ◽  
Bcr Signaling

Abstract The clinical success of PI3K and Btk inhibitors that block upstream BCR signals, has been primarily attributed to inhibition of adhesion and migration of CLL cells. However, the effects of these inhibitors on the proliferative capacity of CLL cells is largely unknown. Interestingly, in vitro BCR triggering does not induce proliferation of CLL cells. Instead, we have found that activated T cell-derived signals, specifically CD40L and IL-21, initiate CLL proliferation in vitro and can be traced in CLL lymph node samples from patients [Pascutti et al., Blood 2013]. Targeting the underlying signaling pathways may be clinically relevant, and therefore we aimed to characterize the molecular mechanisms underlying antigen-independent proliferation. In the present study we applied CD40L/IL-21 stimulation to induce proliferation, and tested various specific kinase inhibitors for blocking potential. Surprisingly, the Btk inhibitor ibrutinib significantly suppressed CD40L/IL-21-induced proliferation (Figure 1). Similarly, inhibition of PI3Kδ with idelalisib dampened proliferation. While neither ibrutinib nor idelalisib affected CD40L-induced NF-kB or IL-21 induced STAT3 phosphorylation, both compounds efficiently blocked downstream ERK1/2 phosphorylation. Impact of idelalisib and ibrutinib was non-synergistic, suggesting that PI3K and Btk are acting in concert. In contrast with the inhibitory effects of the two compounds above, no effect of CD40L/IL-21 induced proliferation was observed following inhibition of SYK activity with R406 (tamatinib). This strongly suggests a role for PI3K and Btk signaling independent of BCR-signaling. We demonstrate that antigen-independent proliferation completely depends on downstream CDK4-activity, which can be blocked by the CDK4-inhibitor PD0332991. IL-21 signaling is absolutely required for antigen-independent proliferation as treatment with the pan-JAK inhibitor INCB abrogates proliferation. Moreover, immunohistochemical staining of lymph nodes from CLL patients indicated the presence of phospho-STAT3 in CLL cells at lymph node sites, suggesting a contribution of JAK/STAT signaling to in vivo proliferation. In conclusion, our data strongly suggest that non-BCR signals contribute to proliferation of CLL cells. Since the most recent clinical data point to development of resistance against ibrutinib, targeting non-BCR pathways may offer additional venues for treatment. Figure 1. CD40L/IL-21 induced proliferation can be inhibited with kinase inhibitors that target kinases involved in BCR-signaling Figure 1. CD40L/IL-21 induced proliferation can be inhibited with kinase inhibitors that target kinases involved in BCR-signaling Disclosures No relevant conflicts of interest to declare.

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