B-cell receptor (BCR) is a B cell hallmark surface complex regulating multiple cellular processes in normal as well as malignant B cells. Igα (CD79a)/Igβ (CD79b) are essential components of BCR that are indispensable for its functionality, signal initiation, and signal transduction. CD79a/CD79b-mediated BCR signaling is required for the survival of normal as well as malignant B cells via a wide signaling network. Recent studies identified the great complexity of this signaling network and revealed the emerging role of CD79a/CD79b in signal integration. In this review, we have focused on functional features of CD79a/CD79b, summarized signaling consequences of CD79a/CD79b post-translational modifications, and highlighted specifics of CD79a/CD79b interactions within BCR and related signaling cascades. We have reviewed the complex role of CD79a/CD79b in multiple aspects of normal B cell biology and how is the normal BCR signaling affected by lymphoid neoplasms associated CD79A/CD79B mutations. We have also summarized important unresolved questions and highlighted issues that remain to be explored for better understanding of CD79a/CD79b-mediated signal transduction and the eventual identification of additional therapeutically targetable BCR signaling vulnerabilities.

• MeSH
• buněčná membrána MeSH
• kognice MeSH
• mutace MeSH
• receptory antigenů B-buněk * genetika   MeSH
• signální transdukce * MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• antigeny CD19 farmakologie   klasifikace   terapeutické užití   MeSH
• antigeny CD79 farmakologie   terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   terapie   MeSH
• lidé MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• protinádorové látky farmakologie   klasifikace   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• polatuzumab vedotin,
• MeSH
• antigeny CD79 antagonisté a inhibitory   fyziologie   MeSH
• bendamustin hydrochlorid terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   imunologie   MeSH
• imunokonjugáty * terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• monoklonální protilátky terapeutické užití   MeSH
• protinádorové látky terapeutické užití   MeSH
• rituximab terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

New and more specific therapies for non-Hodgkin lymphomas (NHL) are greatly needed, since standard treatment is based on a non-specific and highly toxic chemotherapy combination over 40 years old. The B-cell receptor (BCR) inhibition is such emerging therapy applicable to various B-cell derived NHL, which were shown to use at least two types of BCR signaling, the “chronic active” (similar to antigen induced) and “tonic” (analogous to baseline BCR signaling in resting B-cells). Our hypothesis is that individual types of BCR signaling differ substantially in the initial events of BCR activation during phosphorylation of BCR co-receptor molecules CD79A/B and that those differences and detail characteristics can be used as therapeutic targets. We plan to address our hypothesis using modern methods of molecular biology with evaluation of the therapeutic potential using mouse models and primary lymphoma cells. The proposed study has a great potential to identify novel and highly specific targets for BCR inhibition and response prediction.

Současná léčba non-Hodgkinských lymfomů je založena na nespecifických chemoterapeutických kombinacích. Nové léčebné strategie jsou tak nezbytné ke snížení toxicity a zlepšení účinnosti léčby. Signalizace z B-buněčného receptoru je jednou z nich. Lymfomy vzniklé z B-lymfocytů využívají minimálně dva typy signálu z B-buněčného receptoru: “chronicky aktivní“, připomínající antigenem spuštěnou signalizaci, a “tonický”, nutný k základnímu přežití B-lymfocytů. Předpokládáme, že typy signalizace z B-Buněčného receptoru se u lymfomů zásadně liší v úvodní fázi, kdy dochází k fosforylaci koreceptorových molekul B-buněčného receptoru CD79A/B a iniciaci signálu. S využitím nových molekulárně biologických metod a pokročilých modelů plánujeme popsat potenciál využití těchto charakteristik signalizace k cílené léčbě lymfomů. Výsledky získané analýzou na modelových buněčných liniích budou ověřeny na myších modelech a primárních nádorových buňkách. Navrhovaná studie má velký potenciál popsat nové vysoce specifické terapeutické cíle u lymfomů s predikcí odpovědi na inhibici B-buněčného receptoru.

• Klíčová slova
• léčba, therapy, non-hodgkinský lymfom, NHL, DLBCL, B-buněčný receptor, signalizace, ITAM, CD79A, CD79B, Src kinázy, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, DLBCL, B-cell receptor, BCR, signal initiation, Immunoreceptor tyrosine-based activation motif, ITAM, CD79A, CD79B, Src family of kinases, NHL, difuzní velkobuněčný B-lymfom,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Lymfómy MALT (Mucosa - Associated Lymphoid Tissue) typu sú vzácne neoplazmy, ktoré vznikajú malígnou transformáciou slizničného lymfatického tkaniva MALT. Predstavujú 5 % všetkých non-Hodgkinových lymfómov, pričom viac ako 2/3 z nich sa vyskytujú v tráviacom trakte. V súvislosti s ich vznikom má patogenetický význam infekcia žalúdka Helicobacterom pylori (HP). Na stanovenie diagnózy je potrebné endoskopické vyšetrenie gastrointestinálneho traktu s histologickým vyšetrením bioptickej vzorky (morfológia a imunohistochémia). K stanoveniu diagnózy veľkou mierou prispieva aj prietoková cytometria, ktorá je užitočná na potvrdenie monoklonality ochorenia (unimodálnou expresiou jedného typu ľahkých reťazcov kappa alebo lambda) a určenie B-bunkového antigénového profilu spojeného s uvedenou diagnózou (CD19+, CD20+, CD22+, CD24+, CD79a+, HLA-Dr+).

MALT lymphomas (Mucosa - Associated Lymphoid Tissue) are rare neoplasms that arise from a malignant transformation of mucosa lymph tissue MALT. Accounting for about 5 % of all non-Hodgkin lymphomas, more than 2/3 of them occur in gastrointestinal tract. Gastric infection of Helicobacter pylori (HP) plays an important role in its pathogenesis. To determine the diagnosis of MALT lymphoma it is essential to perform an endoscopic examination followed by the histological examination of a bioptic specimen (morphology and immunohistochemistry). Flow cytometry greatly contributes to the diagnosis and is usefull in verification of tumor population monoclonality (unimodal expression of one type of light chains, kappa or lambda) and in determination of B-cell antigen profile associated with this diagnosis (CD19+, CD20+, CD22+, CD24+, CD79a+, HLA-Dr+).

Východisko. Difuzní velkobuněčné B lymfomy tvoří heterogenní skupinu lymfomů, která zahrnuje různé nádory odlišující se původem,morfologickým obrazema klinickým chováním. Difuzní velkobuněčné Blymfomy jsou nověji členěny do dvou velkých, prognosticky relevantních podskupin s odlišnou genovou expresí. Zatím však nebyly detegovány klíčové geny, jejichž vyšetření by umožnilo tyto lymfomy typizovat v běžné diagnostické praxi. Cílem práce bylo sledovat genetické změny a expresi několika genů zúčastněných na onkogenezi velkobuněčných lymfomů. Metody a výsledky. V práci jsme analyzovali soubor 31 nemocných s difuzními velkobuněčnými B lymfomy, u kterých jsme měli k dispozici základní klinická data včetně sledování v průběhu nemoci. V imunohistochemickém vyšetření jsme použili panel protilátek proti CD20, CD79a, BCL-2, CD10, Ki-67 a TP53. Metodou FISH jsme vyšetřovali translokaci t(14;18) a zlom v oblasti genu BCL6 (3q27) signalizující translokace t(3;?) s variabilními translokačními partnery. Metodou PCR jsme vyšetřovali translokaci t(14;18) a klonální přestavbu těžkého řetězce imunoglobulinu a lehkého řetězce kappa. Závěry. Exprese BCL-2 proteinu souvisela s klinicky nepříznivým průběhemchoroby. Exprese ostatních vyšetřených markerů s klinickým chováním nádorů nekorelovala jednoznačně. Nádory, které měly histogenetickou souvislost s folikulárním lymfomem (kompozitní nádory tvořené velkobuněčným difuzním a folikulárním lymfomem) měly v souboru zřetelně vyšší mortalitu než nádory vzniklé de novo. S nepříznivým průběhem choroby souvisely rovněž vyšší hodnoty Mezinárodního prognostického indexu (IPI).

Background. Diffuse large B-cell lymphomas represent a heterogeneous group of tumors with a different origin, morphological findings and a variable clinical prognosis. These tumors have been recently classified into two prognostically relevant subgroups differing in the gene expression. The key genes suitable for routine diagnostics of DLBCL have not been yet identified. The aim of this work was to study changes and expression of several genes and proteins participating in the genesis of DLBCL. Methods and Results. We analysed a group of 31 patients with diffuse large B-cell lymphomas. Basic clinical data including follow-up of the patients were available. Tumors were examined by a panel of immunohistochemical reactions with antibodies against CD20, CD79a, BCL-2, BCL-6, CD10, Ki-67 and TP53. FISH was used to detect a translocation t(14;18)(q32;q21) and/or a break in BCL6 region (3q27) suggestive of a translocation with a variable translocation partner t(3;?). PCR was utilized to detect the translocation t(14;18) and a clonal rearrangement of heavy and/or kappa chain of the immunoglobin genes. Conclusions. The expression of BCL-2 protein appeared to correlate with a higher mortality rate. The expression of other proteins examined in the study did not correspond significantly with the clinical development of the disease. Tumors with follicular lymphoma as a component had significantly higher mortality rate than the tumors developing de novo. Moreover, higher mortality was evident in cases with higher values of the International Prognostic Index (IPI).

• MeSH
• B-buněčný lymfom diagnóza   genetika   MeSH
• exprese genu MeSH
• finanční podpora výzkumu jako téma MeSH
• hybridizace in situ fluorescenční metody   MeSH
• imunohistochemie MeSH
• lidé MeSH
• polymerázová řetězová reakce metody   MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH
• srovnávací studie MeSH

Early identification of resistant cancer cells is currently a major challenge, as their expansion leads to refractoriness. To capture the dynamics of these cells, we made a comprehensive analysis of disease progression and treatment response in a chronic lymphocytic leukemia (CLL) patient using a combination of single-cell and bulk genomic methods. At diagnosis, the patient presented with unfavorable genetic markers, including notch receptor 1 (NOTCH1) mutation and loss(11q). The initial and subsequent treatment lines did not lead to a durable response and the patient developed refractory disease. Refractory CLL cells featured substantial dysregulation in B-cell phenotypic markers such as human leukocyte antigen (HLA) genes, immunoglobulin (IG) genes, CD19 molecule (CD19), membrane spanning 4-domains A1 (MS4A1; previously known as CD20), CD79a molecule (CD79A) and paired box 5 (PAX5), indicating B-cell de-differentiation and disease transformation. We described the clonal evolution and characterized in detail two cell populations that emerged during the refractory disease phase, differing in the presence of high genomic complexity. In addition, we successfully tracked the cells with high genomic complexity back to the time before treatment, where they formed a rare subpopulation. We have confirmed that single-cell RNA sequencing enables the characterization of refractory cells and the monitoring of their development over time.

• MeSH
• analýza jednotlivých buněk * metody   MeSH
• chemorezistence genetika   MeSH
• chronická lymfatická leukemie * genetika   patologie   MeSH
• lidé MeSH
• sekvenční analýza RNA MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Permanent irritation of the peritoneum during peritoneal dialysis (PD) treatment leads to local chronic inflammation and subsequently activation of processes driving fibrogenesis in the long-term. The aim of the study was to compare the peritoneal effluent transcriptome of 20 patients treated less and 13 patients treated more than 2 years using microarray analysis. An increased expression of genes associated with an immune response was observed in long-term treated patients with well preserved peritoneal function, when compared to patients treated less than 2 years. From 100 genes highly expressed in long-term patients, a significant up-regulation of six was found by RT-qPCR: LY9 (lymphocyte antigen 9), TNSFR4 (tumor necrosis factor receptor superfamily, member 4), CD 79A (CD79a molecule), CCR7 (chemokine C-C receptor 7), CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) and IL2RA (interleukin 2 receptor alpha chain). Furthermore, the effluent cell population was analysed. A positive relationship between the number of granulocytes and NK cells on one hand, and duration of PD treatment on the other, was shown. We conclude, that the mechanisms of adaptive immunity promoting T helper 2 cells response are activated in the long-term before functional alterations develop. It consequently might trigger the fibrosis promoting processes.

• MeSH
• adaptivní imunita genetika   MeSH
• ascitická tekutina imunologie   metabolismus   MeSH
• časové faktory MeSH
• fibróza MeSH
• kontinuální ambulantní peritoneální dialýza škodlivé účinky   MeSH
• lidé MeSH
• nádory ledvin terapie   MeSH
• peritoneální dialýza škodlivé účinky   MeSH
• peritoneum imunologie   metabolismus   patologie   MeSH
• regulace genové exprese MeSH
• stanovení celkové genové exprese MeSH
• transkriptom MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Long-term peritoneal dialysis (PD) is associated with functional and structural alterations of the peritoneal membrane. Inflammation may be the key moment, and, consequently, fibrosis may be the end result of chronic inflammatory reaction. The objective of the present study was to identify genes involved in peritoneal alterations during PD by comparing the transcriptome of peritoneal cells in patients with short- and long-term PD. Peritoneal effluent of the long dwell of patients with stable PD was centrifuged to obtain peritoneal cells. The gene expression profiles of peritoneal cells using microarray between patients with short- and long-term PD were compared. Based on microarray analysis, 31 genes for quantitative RT-PCR validation were chosen. A 4-h peritoneal equilibration test was performed on the day after the long dwell. Transport parameters and protein appearance rates were assessed. Genes involved in the immune system process, immune response, cell activation, and leukocyte and lymphocyte activation were found to be substantially upregulated in the long-term group. Quantitative RT-PCR validation showed higher expression of CD24, lymphocyte antigen 9 (LY9), TNF factor receptor superfamily member 4 (TNFRSF4), Ig associated-alpha (CD79A), chemokine (C-C motif) receptor 7 (CCR7), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), and IL-2 receptor-alpha (IL2RA) in patients with long-term PD, with CD24 having the best discrimination ability between short- and long-term treatment. A relationship between CD24 expression and genes for collagen and matrix formation was shown. Activation of CD24 provoked by pseudohypoxia due to extremely high glucose concentrations in dialysis solutions might play the key role in the development of peritoneal membrane alterations.

• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci ledvin genetika   metabolismus   terapie   MeSH
• peritoneální dialýza * MeSH
• peritoneum * metabolismus   MeSH
• průřezové studie MeSH
• regulace genové exprese MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkriptom * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH

Differentiation during hematopoiesis leads to the generation of many cell types with specific functions. At various stages of maturation, the cells may change pathologically, leading to diseases including acute leukemias (ALs). Expression levels of regulatory molecules (such as the IKZF, GATA, HOX, FOX, NOTCH and CEBP families, as well as SPI-1/PU1 and PAX5) and lineage-specific molecules (including CD2, CD14, CD79A, and BLNK) may be compared between pathological and physiological cells. Although the key steps of differentiation are known, the available databases focus mainly on fully differentiated cells as a reference. Precursor cells may be a more appropriate reference point for diseases that evolve at immature stages. Therefore, we developed a quantitative real-time polymerase chain reaction (qPCR) array to investigate 90 genes that are characteristic of the lymphoid or myeloid lineages and/or are thought to be involved in their regulation. Using this array, sorted cells of granulocytic, monocytic, T and B lineages were analyzed. For each of these lineages, 3-5 differentiation stages were selected (17 stages total), and cells were sorted from 3 different donors per stage. The qPCR results were compared to similarly processed AL cells of lymphoblastic (n=18) or myeloid (n=6) origins and biphenotypic AL cells of B cell origin with myeloid involvement (n=5). Molecules characteristic of each lineage were found. In addition, cells of a newly discovered switching lymphoblastic AL (swALL) were sorted at various phases during the supposed transdifferentiation from an immature B cell to a monocytic phenotype. As demonstrated previously, gene expression changed along with the immunophenotype. The qPCR data are publicly available in the LeukoStage Database in which gene expression in malignant and non-malignant cells of different lineages can be explored graphically and differentially expressed genes can be identified. In addition, the LeukoStage Database can aid the functional analyses of next-generation sequencing data.

• MeSH
• akutní bifenotypická leukemie genetika   imunologie   patologie   MeSH
• B-lymfocyty imunologie   patologie   MeSH
• buněčná diferenciace genetika   MeSH
• buněčný rodokmen genetika   MeSH
• čipová analýza tkání MeSH
• hematopoéza genetika   MeSH
• imunofenotypizace MeSH
• lidé MeSH
• nádorové proteiny biosyntéza   MeSH
• regulace genové exprese u leukemie MeSH
• T-lymfocyty imunologie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH