GCB DLBCL subtype
Dotaz
Zobrazit nápovědu
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.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.
- MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- signální transdukce MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Primární kostní lymfom je vzácná a překvapivá diagnóza. Představujeme případ 37leté ženy s difuzním velkobuněčným B-lymfomem (DLBCL) křížové kosti doplněný o snímky ze zobrazovacích metod a bioptický nález. Několik let před hospitalizací pacientku postihovaly spontánní fraktury a povšechné bolesti, zejména beder. Na základě toho bylo provedeno biochemické vyšetření krve, krevní obraz, třífázová scintigrafie skeletu pomocí 99mTc-HDP SPECT/CT, CT a MRI pánve. Biopsie z kosti křížové byla zpracována metodou formalinové fixace a zalití do parafínového bloku (FFPE), řezy byly obarveny pomocí standardních a imunohistochemických metod. Ke stagingu lymfomu bylo provedeno 18F-FDG PET/CT vyšetření. V 1. a 2. fázi třífázové kostní scintigrafie nebyla pozorována odchylka v krevní cirkulaci či tkáňové perfuzi. Avšak v kostní fázi SPECT/low dose CT byl pozorován defekt akumulace s lemem akumulace zvýšené, odpovídající ložisku osteolýzy s lemem zvýšené kostní přestavby. Histopatologicky byla stanovena diagnóza DLBLC, germinal center B-cell like (GCB-like) subtyp. Třífázová scintigrafie skeletu výrazně přispěla k odhalení primárního DLBCL v poměrně neobvyklé lokalizaci. Časné odhalení DLBCL a následná kombinovaná léčba vedla ke stabilizaci onemocnění.
Primary bone lymphoma is a very rare and surprising diagnosis. We present a case of 37years old woman with primary sacral diffuse large B-cell lymphoma (DLBCL), supplemented with images from imaging studies and histopathological report. Patient suffered from spontaneous fractures and pain for several years prior to the last hospitalisation. She underwent analysis of biochemical profile and blood count, a three-phase bone scintigraphy, pelvic CT and MRI. Biopsy from sacral bone was processed as formalin-fixed paraffin-embeded blocs (FFPE), sections were stained by standard and immunohistochemical methods. 18F-FDG PET/CT scan was performed for lymphoma staging. Three-phase bone scintigraphy did not show abnormity in blood circulation or tissue perfusion in the course of the first and second phase. However, in the delayed phase, we observed an accumulation defect with rim of higher radiotracer accumulation on SPECT/low dose CT corresponding to osteolytic focus with rim of increased bone remodelling. Histopathological examination led to diagnosis of DLBCL, germinal center B-cell like (GBC-like) subtype. A three-phase bone scintigraphy significantly helped to disclose DLBCL in atypical location. Early diagnosis of DLBCL was followed by appropriate treatment, which resulted in stabilization of disease.
- Klíčová slova
- třífázová scintigrafie skeletu,
- MeSH
- diagnostické zobrazování metody MeSH
- difúzní velkobuněčný B-lymfom * diagnostické zobrazování diagnóza MeSH
- dospělí MeSH
- křížová kost diagnostické zobrazování patologie MeSH
- lidé MeSH
- radioisotopová scintigrafie metody MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky 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
Difuzní velkobuněčný B lymfom (diffuse large B-cell lymphoma, DLBCL) tvoří v České republice přibližně 40 % všech nově diagnostikovaných systémových nehodgkinských lymfomů a je považován za vyléčitelné onemocnění kombinací imunochemoterapie RCHOP (rituximab, cyklofosfamid, doxorubicin, vincristin, prednison). Na druhu stranu přibližně 40 % pacientů má relabující onemocnění se špatnou prognózou. Recentní genetické studie ukázaly pomocí sekvenování nové generace, že morfologicky poměrně uniformní jednotka DLBCL je tvořena až sedmi genetickými skupinami s odlišným biologickým chováním a odpovědí na RCHOP. Tyto genetické skupiny jsou více či méně zastoupeny v dříve definovaných kategoriích ABC-DLBCL (ABC - aktivované B lymfocyty) nebo GCB-DLBCL (GCB - B lymfocyty germinálního centra). Klinický průběh a citlivost k imunochemoterapii je dána alterací různých signálních drah B lymfocytů, které korelují s konkrétním genetickým subtypem. Tyto odlišné alterace jsou však u jednotlivých typů potenciálně využitelné k cílené léčbě.
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all newly diagnosed systemic non-Hodgkin's lymphomas in the Czech Republic and is considered a curable disease with a combination of RCHOP immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). On the other hand, approximately 40% of patients have relapsing disease with a poor prognosis. Recent genetic studies have shown by next generation sequencing that the morphologically relatively uniform DLBCL unit consists of up to seven genetic groups with different biological behavior and response to RCHOP These genetic groups are more or less represented in the previously defined categories ABC-DLBCL (ABC - activated B lymphocytes) or GCB-DLBCL (GCB - germinal center B-cell). The clinical course and sensitivity to immunochemotherapy is determined by the alteration of different B cell signaling pathways that correlate with a particular genetic subtype. However, these different alterations are potentially useful for targeted treatment in each type.
- MeSH
- difúzní velkobuněčný B-lymfom * diagnóza genetika klasifikace MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550).Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127-37. ©2017 AACR.
- MeSH
- deoxycytidin aplikace a dávkování analogy a deriváty MeSH
- difúzní velkobuněčný B-lymfom farmakoterapie patologie MeSH
- dospělí MeSH
- etoposid aplikace a dávkování MeSH
- Kaplanův-Meierův odhad MeSH
- lidé středního věku MeSH
- lidé MeSH
- organoplatinové sloučeniny aplikace a dávkování MeSH
- přežití bez známek nemoci MeSH
- prognóza * MeSH
- proporcionální rizikové modely MeSH
- protokoly protinádorové kombinované chemoterapie aplikace a dávkování škodlivé účinky MeSH
- rituximab aplikace a dávkování MeSH
- senioři MeSH
- thalidomid aplikace a dávkování škodlivé účinky analogy a deriváty MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
Diffuse large B-cell lymphoma (DLBCL) consists of at least two biologically and pathogenetically different subtypes, the germinal centre B-cell (GCB) and the activated B cell type (ABC). It has been suggested that immunohistochemistry can discriminate these subtypes as well. The aim of this study was to verify the validity of the most commonly used Hans algorithm in patients with DLBCL treated with anthracycline- based chemotherapy with rituximab. Immunohistochemical staining using standard protocols was performed on formalin fixed paraffin-embedded tissues. CD20, CD5, CD23, BCL2, CD10, BCL6, MUM1 and Ki67 antibodies were applied. Out of 120 examined cases 52 patients were evaluated as GCB type and 68 patients as having non-GCB, out of a set of 99 patients treated with immunochemotherapy 45 patients with GCB and 54 patients with non-GCB DLBCL were identified. In this set of patients, there was no statistically significant difference neither in overall survival (OS) (HR 1.47 95% CI 0.51-2.63; p=0.45) nor in progression free survival (PFS) (HR 1.57, 95 % CI 0.76-3.22; p=0.731) between both groups.
- MeSH
- algoritmy * MeSH
- cyklofosfamid aplikace a dávkování MeSH
- difúzní velkobuněčný B-lymfom farmakoterapie mortalita patologie MeSH
- dospělí MeSH
- doxorubicin aplikace a dávkování MeSH
- imunoenzymatické techniky MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- mladý dospělý MeSH
- myší monoklonální protilátky aplikace a dávkování MeSH
- následné studie MeSH
- prednison aplikace a dávkování MeSH
- prognóza MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- vinkristin aplikace a dávkování MeSH
- zárodečné centrum lymfatické uzliny patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
