Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs' expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs' expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL.

• Klíčová slova
• B-cells, circRNA, gene expression, lymphoma, miRNA,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The currently valid molecular genetic subclassification of patients with diffuse large B-cell lymphoma (DLBCL) into three prognostic subgroups based on expression profiling has been the objective of numerous genetic studies. In routine clinical practice, however, expression profiling technology remains unavailable for the most of centers. Apart from the technology, in some cases molecular genetic laboratories have problems obtaining high-quality material, i.e. fresh tissues, for RNA isolation to determine gene expression. One possibility is to determine the gene expression from RNA obtained by isolation from formalin-fixed, paraffin-embedded (FFPE) tissue. This pilot study aimed at isolating RNA from FFPE in patients diagnosed with DLBCL and verifying the potential use of such RNA for the expression analysis of 7 selected genes. Although the study showed that it is possible to isolate RNA and determine the expression of the selected genes from archival material, the values of relative expression of some genes in the set were too variable to be used for unambiguous prognostic classification. It was confirmed that retrospective analyses of selected genes may be performed with sufficient material obtained, and that properly archived blocks may be used for molecular biology analyses even after 8 years.

• MeSH
• difúzní velkobuněčný B-lymfom genetika   MeSH
• formaldehyd MeSH
• geny nádorové * MeSH
• lidé MeSH
• odběr biologického vzorku MeSH
• parafín MeSH
• pilotní projekty MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• RNA izolace a purifikace   MeSH
• stanovení celkové genové exprese * MeSH
• zalévání tkání do parafínu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• formaldehyd MeSH
• parafín MeSH
• RNA MeSH

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) accounts for up to 40% of all non-Hodgkin's lymphomas diagnosed in the western hemisphere. Determination of the gene expression profile has confirmed the physiological heterogeneity of the disease and defined three molecular prognostic subgroups - germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal B-cell lymphoma (PMBL) - with different gene expression and prognosis. METHODS AND RESULTS: This review covers current knowledge on the most frequent recurrent cytogenetic and molecular cytogenetic aberrations in molecular DLBCL subgroups. CONCLUSIONS: Cytogenetic and molecular cytogenetic techniques used to determine nonrandom chromosomal aberrations in patients with DLBCL have revealed the incidence of frequent cytogenetic aberrations in the subgroups reported, suggesting their potential use for more accurate prognostic stratification of DLBCL, contributing to personalized selection of the most effective therapy.

• MeSH
• chromozomální aberace * MeSH
• difúzní velkobuněčný B-lymfom klasifikace   genetika   MeSH
• dospělí MeSH
• geny bcl-2 genetika   MeSH
• lidé MeSH
• nádorová transformace buněk genetika   MeSH
• nádory mediastina genetika   MeSH
• prognóza MeSH
• protoonkogenní proteiny c-bcl-6 genetika   MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protoonkogenní proteiny c-bcl-6 MeSH

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2-specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.

• MeSH
• dánio pruhované MeSH
• difúzní velkobuněčný B-lymfom farmakoterapie   genetika   metabolismus   patologie   MeSH
• dimethyl fumarát farmakologie   MeSH
• ferroptóza účinky léků   MeSH
• lidé MeSH
• myši MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• NF-kappa B genetika   metabolismus   MeSH
• peroxidace lipidů účinky léků   genetika   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   genetika   MeSH
• transkripční faktor STAT3 genetika   metabolismus   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dimethyl fumarát MeSH
• nádorové proteiny MeSH
• NF-kappa B MeSH
• STAT3 protein, human MeSH Prohlížeč
• transkripční faktor STAT3 MeSH

Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.

• MeSH
• B-lymfocyty MeSH
• chronická lymfatická leukemie * MeSH
• difúzní velkobuněčný B-lymfom * genetika   MeSH
• imunoglobulin M MeSH
• myši MeSH
• receptory antigenů B-buněk MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• imunoglobulin M MeSH
• receptory antigenů B-buněk MeSH

Diffuse large B-cell lymphoma (DLBCL) represents a curable disease with a 60-70% chance of cure with current R-CHOP chemoimmunotherapy. However, 30-40% of patients are refractory or relapsing. Many attempts failed to improve the outcome of DLBCL patients, including the intensification of R-CHOP regimen, consolidation, or maintenance therapy since the introduction of R-CHOP in 2000. Better understanding of both molecular biology of lymphoma cells and the tumor microenvironment raised the hope for future improvement of DLBCL patients' survival. Novel molecular findings have initiated clinical trials exploring targeted therapy based on driver genetic alterations with an intent to improve survival of high-risk subsets of patients. But the preliminary results remain ambiguous. The approach "agnostic" to specific molecular alterations of lymphoma cell includes antibody-drug conjugates (especially polatuzumab vedotin), immunotherapy comprising different antibodies with immunomodulatory effect (tafasitamab, lenalidomide), and T-cell engaging therapy (bispecific antibodies, early use of CAR T-cell). This approach could increase the cure rates and change the current therapeutic paradigm. However, better prognostic stratification, smarter designs of clinical trials, modification of endpoints including the use of ctDNA are needed. This review covers the complexity of DLBCL management.

• Klíčová slova
• R-CHOP, agnostic therapy, diffuse large B-cell lymphoma, first-line therapy, polatuzumab vedotin, tailored therapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.

• MeSH
• adenin analogy a deriváty   MeSH
• apoptóza účinky léků   MeSH
• difúzní velkobuněčný B-lymfom klasifikace   farmakoterapie   genetika   patologie   MeSH
• fixní kombinace léků MeSH
• fosfatidylinositol-3-kinasy genetika   metabolismus   MeSH
• fosfohydroláza PTEN nedostatek   genetika   MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• myši MeSH
• NF-kappa B antagonisté a inhibitory   genetika   metabolismus   MeSH
• orgánová specificita MeSH
• oxadiazoly farmakologie   MeSH
• piperidiny farmakologie   MeSH
• proteinkinasa BTK MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   genetika   metabolismus   MeSH
• protoonkogenní proteiny c-myc antagonisté a inhibitory   genetika   metabolismus   MeSH
• pyrazoly farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• pyrroly farmakologie   MeSH
• regulace genové exprese u nádorů * MeSH
• screeningové testy protinádorových léčiv MeSH
• signální transdukce MeSH
• synergismus léků MeSH
• tyrosinkinasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenin MeSH
• AZD8835 MeSH Prohlížeč
• Btk protein, mouse MeSH Prohlížeč
• capivasertib MeSH Prohlížeč
• fixní kombinace léků MeSH
• fosfohydroláza PTEN MeSH
• ibrutinib MeSH Prohlížeč
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• MYC protein, human MeSH Prohlížeč
• NF-kappa B MeSH
• oxadiazoly MeSH
• piperidiny MeSH
• proteinkinasa BTK MeSH
• protinádorové látky MeSH
• protoonkogenní proteiny c-akt MeSH
• protoonkogenní proteiny c-myc MeSH
• PTEN protein, human MeSH Prohlížeč
• pyrazoly MeSH
• pyrimidiny MeSH
• pyrroly MeSH
• tyrosinkinasy MeSH

Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.

• MeSH
• cyklofosfamid terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   genetika   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• receptory IgG genetika   MeSH
• rituximab terapeutické užití   MeSH
• vinkristin terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cyklofosfamid MeSH
• FCGR2B protein, human MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• obinutuzumab MeSH Prohlížeč
• receptory IgG MeSH
• rituximab MeSH
• vinkristin MeSH

The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3, which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC. Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase-associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition-induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including PLK1. Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab in vitro, increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. SIGNIFICANCE: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression.

• MeSH
• antigeny CD20 MeSH
• apoptóza MeSH
• difúzní velkobuněčný B-lymfom farmakoterapie   genetika   metabolismus   patologie   MeSH
• fosforylace MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• proliferace buněk MeSH
• protinádorové látky imunologicky aktivní farmakologie   MeSH
• protoonkogenní proteiny c-myc genetika   metabolismus   MeSH
• protoonkogenní proteiny c-pim-1 antagonisté a inhibitory   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• rituximab farmakologie   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD20 MeSH
• inhibitory proteinkinas MeSH
• MYC protein, human MeSH Prohlížeč
• protinádorové látky imunologicky aktivní MeSH
• proto-oncogene proteins pim MeSH Prohlížeč
• protoonkogenní proteiny c-myc MeSH
• protoonkogenní proteiny c-pim-1 MeSH
• rituximab MeSH

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes (complete response [CR] rates with standard salvage therapy gemcitabine plus oxaliplatin [GemOx], ∼30%; median overall survival [OS], 10 to 13 months). Patients with refractory disease fare worse (CR rate with salvage therapy, 7%; median OS, 6 months). Epcoritamab, a CD3×CD20 bispecific antibody approved for R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE NHL-2 trial evaluating epcoritamab plus GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL. Patients received 48 mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given once every 2 weeks for 8 doses. The primary end point was overall response rate (ORR). As of 15 December 2023, 103 patients were enrolled (median follow-up, 13.2 months; median age, 72 years). Patients had challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior chimeric antigen receptor T-cell therapy, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR and CR rate were 85% and 61%, respectively. Median duration of CR and OS were 23.6 and 21.6 months, respectively. Common treatment-emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab plus GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT-ineligible R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT04663347.

• MeSH
• deoxycytidin * analogy a deriváty   aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   mortalita   patologie   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• oxaliplatin aplikace a dávkování   škodlivé účinky   MeSH
• protilátky bispecifické * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• záchranná terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• Názvy látek
• deoxycytidin * MeSH
• oxaliplatin MeSH
• protilátky bispecifické * MeSH