B-cell suppression
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Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of patients with DLBCL, first-line multiagent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. In this study, a compound library, targeting epigenetic modulators, was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B-cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 expression and thus to protect GCB-DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB-DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.
The immunoregulatory properties of mesenchymal stem cells (MSCs) have been well documented in various models in vitro and in vivo. Furthermore, a population of regulatory B cells (Bregs) that produce relatively high concentrations of IL-10 has been recently described. To study the relationship between MSCs and Bregs, we analyzed the effects of MSCs on IL-10 production by lipopolysaccharide (LPS)-activated mouse B cells. The production of IL-10 by B cells remained preserved in the presence of MSCs and was even significantly enhanced by IFN-γ. However, the production of IL-10 was strongly suppressed in cultures containing MSCs and IFN-γ. Preincubation of MSCs, but not of B cells, with IFN-γ induced the suppression of IL-10 secretion in cultures containing MSCs and B cells. The supernatants from IFN-γ-treated MSCs had no inhibitory effect, and the suppression of IL-10 production was abrogated if the MSCs and B cells were separated in a transwell system. Analysis of the gene expression of IFN-γ- or IFN-γ and LPS-treated MSCs revealed a strong upregulation of genes for indoleamine-2,3-dioxygenase (IDO), cyclooxygenase-2 (Cox-2) and programmed cell death-ligand 1 (PD-L1). While the inhibition of IDO activity or the inclusion of the neutralization monoclonal antibody anti-PD-L1 did not abrogate the suppression, indomethacin, an inhibitor of Cox-2, completely inhibited the MSC-mediated suppression of IL-10 production. Accordingly, the production of IL-10 by B cells was inhibited by exogenous prostaglandin E2. The results thus suggest that IFN-γ-treated MSCs strongly inhibit IL-10 production by activated B cells by a mechanism requiring cell contact and involving the Cox-2 pathway.
- MeSH
- aktivace lymfocytů účinky léků MeSH
- antigeny CD274 antagonisté a inhibitory genetika imunologie MeSH
- B-lymfocyty cytologie účinky léků imunologie MeSH
- cyklooxygenasa 2 genetika imunologie MeSH
- difuzní komory kultivační MeSH
- dinoproston farmakologie MeSH
- indolamin-2,3,-dioxygenasa genetika imunologie MeSH
- indomethacin farmakologie MeSH
- inhibitory cyklooxygenasy farmakologie MeSH
- interferon gama farmakologie MeSH
- interleukin-10 antagonisté a inhibitory genetika imunologie MeSH
- kokultivační techniky MeSH
- kultivační média speciální farmakologie MeSH
- lipopolysacharidy farmakologie MeSH
- mezenchymální kmenové buňky cytologie účinky léků imunologie MeSH
- mezibuněčná komunikace imunologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- neutralizující protilátky farmakologie MeSH
- primární buněčná kultura MeSH
- regulace genové exprese MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The aim of this review was to summarize recent knowledge of the structure and function of a transcriptional repressor, B lymphocyte induced maturation protein 1 (BLIMP1) and its participation in the pathogenesis of B lymphomas. Methods and results. This review summarizes the structure and function of BLIMP1, its major target genes and its role as a tumour suppressor in B cell lymphomas. We review our recent data implicating the loss of BLIMP1α as an important step in the pathogenesis of the Epstein-Barr virus (EBV) associated B cell lymphomas. Conclusions. BLIMP1 is a transcriptional repressor essential for the differentiation of germinal centre (GC) B cells to plasma cells. The loss of BLIMP1 in GC B cells could contribute to the pathogenesis of EBV-associated lymphomas by preventing plasma cell differentiation and viral replication.
- MeSH
- B-buněčný lymfom genetika virologie MeSH
- buněčná diferenciace genetika MeSH
- down regulace MeSH
- imunoglobuliny biosyntéza MeSH
- lidé MeSH
- plazmatické buňky fyziologie MeSH
- regulace genové exprese u nádorů MeSH
- represorové proteiny fyziologie genetika MeSH
- tumor supresorové geny fyziologie MeSH
- virus Epsteinův-Barrové fyziologie MeSH
- zárodečné centrum lymfatické uzliny fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is driven by aberrant activation of the B-cell receptor (BCR) and the TLR/MyD88 signaling pathways. The heat-shock protein HSP110 is a candidate for their regulation as it stabilizes MyD88. However, its role in overall BCR signaling remains unknown. Here, we used first-in-class HSP110 inhibitors to address this question. HSP110 inhibitors decreased the survival of several ABC-DLBCL cell lines in vitro and in vivo, and reduced the phosphorylation of BCR signaling kinases, including BTK and SYK. We identified an interaction between HSP110 and SYK and demonstrated that HSP110 promotes SYK phosphorylation. Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients.
- MeSH
- chinazoliny MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie metabolismus patologie MeSH
- fosforylace účinky léků MeSH
- kinasa Syk * antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové buňky kultivované MeSH
- proteiny tepelného šoku HSP110 * metabolismus MeSH
- pyrimidiny farmakologie MeSH
- receptory antigenů B-buněk * metabolismus MeSH
- signální transdukce * účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.
- MeSH
- B-buněčný lymfom genetika patologie MeSH
- buněčné klony MeSH
- CRISPR-Cas systémy genetika MeSH
- genetické asociační studie MeSH
- genetické testování metody MeSH
- genová dávka MeSH
- geny nádorové MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- receptory antigenů B-buněk metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- reprodukovatelnost výsledků MeSH
- transpozibilní elementy DNA genetika MeSH
- tumor supresorové geny MeSH
- ztráta heterozygozity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl pyruvate (EP) is a derivative of pyruvic acid and found to have potent anti-tumor properties. Despite its potential benefits, the impact of EP on DLBCL remains ambiguous. Our objective is to elucidate the role of EP in modulating the development of DLBCL. Analysis of cholecystokinin-8 (CCK-8) revealed that treatment with EP significantly diminished the viability of DLBCL cells. Furthermore, EP administration suppressed colony formation and hindered cell adhesion and invasion in DLBCL cells. Examination of cell cycle progression showed that EP treatment induced arrest at the G1 phase and subsequently reduced the S phase population in DLBCL cells. EP treatment consistently exhibited apoptosis-inducing properties in Annexin-V assays, and notably downregulated the expression of Bcl-2 while increasing levels of proapoptotic cleaved caspase 3 and BAX in DLBCL cells. Additionally, EP treatment decreased the overexpression of c-Jun in c-Jun-transfected DLBCL cells. Further, EP demonstrated DNA-damaging effects in TUNEL assays. In vivo, xenograft animal models revealed that EP treatment significantly mitigated DLBCL tumor growth and suppressed DLBCL cell adhesion to bone marrow stromal cells. In summary, these findings suggest that EP mitigates DLBCL progression by inducing apoptosis, inducing cell cycle arrest, and promoting DNA damage.
- MeSH
- apoptóza účinky léků MeSH
- buněčná adheze * účinky léků MeSH
- difúzní velkobuněčný B-lymfom * farmakoterapie patologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk * účinky léků MeSH
- protoonkogenní proteiny c-jun metabolismus genetika MeSH
- pyruváty * farmakologie terapeutické užití MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
B-lymphopoiesis in FL differs notably from that of adult B-lymphopoiesis in being resistant to suppression by oestrogens due to the lack of expression of oestrogen receptors in B-cell progenitors and precursors. We have transplanted middle-stage FL cells (E14.5) to adult male mice and demonstrated that B-lymphopoiesis derived from FL cells remained resistant to suppression by exogenous oestrogen for several months compared to adult BM cells. This significant difference strongly suggests that the latestage FL environment exerts an inductive action on the haematopoietic stem cells and is mandatory for later sensitivity of B-lymphopoiesis to suppression by oestrogens. The results also provide the first in vivo functional confirmation of a differential responsiveness of FL- and adult BM-derived B-lymphopoiesis to suppression by oestrogens.
- MeSH
- B-lymfocyty fyziologie účinky léků MeSH
- estrogeny farmakologie MeSH
- hematopoetické kmenové buňky fyziologie účinky léků MeSH
- játra fyziologie MeSH
- lymfopoéza fyziologie účinky léků MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- plod anatomie a histologie fyziologie MeSH
- radiační chiméra MeSH
- těhotenství MeSH
- transplantace kmenových buněk MeSH
- životní prostředí MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
Monoklonální protilátky proti CD20+ lymfocytům představují vysoce účinnou léčbu roztroušené sklerózy rychlým potlačením aktivity podmíněné hlavně zánětlivými ději. Progresivní složka onemocnění představuje terapeuticky obtížnější problém - dochází ke kompartmentalizaci zánětu za hematoencefalickou bariéru, zánět se stává difuzní, úlohu hrají degenerativní procesy. Byť nejlepší účinek léčby je při jejím co nejčasnějším zahájení, u části pacientů může být přítomna progrese od počátku onemocnění, nebo jsou diagnostikováni v pokročilé fázi choroby. Deplece CD20+ lymfocytů může i u těchto pacientů progresi oddálit anebo zpomalit. Cílem článku je shrnout patofyziologii, možnosti ovlivnění progrese deplecí B lymfocytů, výsledky klinických studií a budoucí směry léčby progresivní roztroušené sklerózy.
Monoclonal antibodies against CD20+ lymphocytes represent a highly effective treatment of multiple sclerosis by rapidly suppressing activity conditioned mainly by inflammatory processes. The progressive component of the disease presents a therapeutically more difficult problem - inflammation compartmentalizes beyond the blood-brain barrier, inflammation becomes diffuse, and degenerative processes play a role. Although the best effect of treatment is when it is started as early as possible, some patients may have progression from the beginning of the disease or are diagnosed at an advanced stage of the disease. Depletion of CD20+ lymphocytes may delay or slow progression in these patients. The aim of this article is to summarize the pathophysiology, the possibilities of influencing the progression of B lymphocyte depletion, the results of clinical trials and future directions in the treatment of progressive multiple sclerosis.
- Klíčová slova
- ocrelizumab,
- MeSH
- B-lymfocyty * účinky léků MeSH
- humanizované monoklonální protilátky aplikace a dávkování farmakologie MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- progrese nemoci MeSH
- roztroušená skleróza * etiologie farmakoterapie patofyziologie terapie MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Abnormalities of several cell-cycle regulatory genes including cyclin D1, p16CDKN2 and p15CDKN2B have been described in B cell non-Hodgkin's lymphoma (B-NHL). We describe a new B-NHL cell line (Granta 519), with concurrent abnormalities of the cyclin D1, pl6CDKN2 and pl5CDKN2B genes. An independent clinical case of mantle cell NHL (Mc-NHL) with concomitant overexpression of cyclin D1, and deletion of the p16CDKN2 gene was also identified, suggesting that this combination of oncogenic aberration is a pathophysiologic contribution to a subset of NHL cases. More in-depth functional studies of this concept were facilitated by the availability of the cell line Granta 519 which was derived from a case of high-grade NHL and has a mature B cell immunophenotype. Cytogenetic analysis identified translocation t(11;14)(q13;q32) and complex rearrangements involving chromosomes 9p22, 13p21, 17pl1, and 18q21. Molecular analysis identified overexpression of cyclin D1 mRNA and biallelic deletion of the p16CDKN2 and p15CDKN2B genes. To elucidate the effect of these genetic abnormalities on the G1 control of Granta 519 cells, the level and function of the major components of the cyclinD/retinoblastoma (RB) pathway were investigated. Cyclin D1 was dominant among the D-type cyclins, formed abundant complexes with cyclin-dependent kinase (Cdk) Cdk4 rather than Cdk6, and the immunoprecipitated cyclin D1/Cdk4 holoenzyme was active as a pRB kinase. Electroporation of wild-type pl6CDKN2 arrested the Granta 519 cells in G1, consistent with the p16CDKN2 loss as a biologically relevant event during multistep evolution of the tumor, and with the expression of functional pRB. Direct cooperation of these distinct abnormalities to cell-cycle, deregulation in NHL cells was suggested by G1 acceleration upon inducible overexpression of cyclin D1 in a control breast cancer cell line lacking p16CDKN2, an effect which could be prevented by ectopic expression of p16CDKN2. Taken together, these data suggest that concurrent overexpression of cyclin D1 and functional elimination of p16CDKN2 and p15CDKN2B may characterize certain cases of mantle cell NHL, and that cooperation of the abnormalities is likely to provide a growth advantage of the tumour cells through more efficient inactivation of the RB tumor suppressor. Further clinicopathologic studies of this possibility are warranted.
- MeSH
- B-buněčný lymfom genetika MeSH
- cyklin D1 MeSH
- cykliny genetika metabolismus MeSH
- delece genu * MeSH
- imunofenotypizace MeSH
- inhibitor p15 cyklin-dependentní kinasy MeSH
- inhibitor p16 cyklin-dependentní kinasy MeSH
- karyotypizace MeSH
- lidé MeSH
- lidské chromozomy, pár 11 * MeSH
- lidské chromozomy, pár 14 * MeSH
- messenger RNA metabolismus MeSH
- nádorové buňky kultivované MeSH
- nádorové proteiny genetika metabolismus MeSH
- nádorové supresorové proteiny * MeSH
- onkogenní proteiny genetika metabolismus MeSH
- proteiny buněčného cyklu * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- translokace genetická genetika MeSH
- transportní proteiny genetika metabolismus MeSH
- tumor supresorové geny MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
