RESUMO
A 4-year-old female Maltese dog was referred to our veterinary hospital with uveitis and conjunctivitis of the right eye. An ophthalmological evaluation revealed an intraocular mass that appeared to originate from the anterior uvea. Metastasis and regional invasion were not detected with CT examination. Enucleation of the right eye was recommended; however, the owner declined treatment. Six months later, the dog was re-presented with a right facial mass. At presentation, superficial lymph node enlargement was not appreciated, and no apparent alterations were noted on blood analysis or urinalysis. Computed tomography revealed an intraocular mass that invaded the surrounding tissues, including the frontal sinus. Presumed solitary ocular lymphoma with a large B-cell phenotype and Mott cell change was diagnosed via histopathological and immunohistochemical examination of a biopsy of the lesion. As the mass was too large for complete excision, neoadjuvant chemotherapy was administered. Complete remission was achieved using the L-COAP protocol and successful exenteration of the right eye. However, the dog was returned with enlargement of the right retropharyngeal lymph nodes. To the best of our knowledge, this is the first case report of presumed solitary ocular lymphoma with a large B-cell phenotype displaying Mott cell change in a dog. Key clinical message: This is the first reported case of a presumed solitary ocular lymphoma with a large B-cell phenotype and Mott cell change. Although systemic involvement was observed 6 mo after the initial visit, neoadjuvant chemotherapy and exenteration were effective.
Lymphome oculaire solitaire présumé d'origine à grandes cellules B avec modification des cellules de Mott chez un chienUne chienne maltaise de 4 ans a été envoyée à notre hôpital vétérinaire avec une uvéite et une conjonctivite de l'Åil droit. Une évaluation ophtalmologique a révélé une masse intraoculaire qui semblait provenir de l'uvée antérieure. Aucune métastase ni invasion régionale n'ont été détectées par examen CT. Une énucléation de l'Åil droit a été recommandée; cependant, le propriétaire a refusé le traitement. Six mois plus tard, le chien a été présenté à nouveau avec une masse faciale droite. À la présentation, l'augmentation de taille des ganglions lymphatiques superficiels n'a pas été réalisée, et aucune modification apparente n'a été notée sur l'analyse sanguine ou l'analyse d'urine. La tomodensitométrie a révélé une masse intraoculaire qui a envahi les tissus environnants, y compris le sinus frontal. Un lymphome oculaire solitaire présumé avec un phénotype à grandes cellules B et une modification des cellules de Mott a été diagnostiqué via un examen histopathologique et immunohistochimique d'une biopsie de la lésion. Comme la masse était trop importante pour une exérèse complète, une chimiothérapie néoadjuvante a été administrée. Une rémission complète a été obtenue grâce au protocole L-COAP et à une exentération réussie de l'Åil droit. Cependant, le chien a été vu de nouveau avec une hypertrophie des ganglions lymphatiques rétropharyngés droits. À notre connaissance, il s'agit du premier cas rapporté de lymphome oculaire solitaire présumé avec un phénotype à grandes cellules B présentant une modification des cellules de Mott chez un chien.Message clinique clé :Il s'agit du premier cas rapporté de lymphome oculaire solitaire présumé avec un phénotype à grandes cellules B et une modification des cellules de Mott. Bien qu'une atteinte systémique ait été observée 6 mois après la visite initiale, la chimiothérapie néoadjuvante et l'exentération ont été efficaces.(Traduit par Dr Serge Messier).
Assuntos
Doenças do Cão , Neoplasias Oculares , Animais , Cães , Doenças do Cão/patologia , Doenças do Cão/diagnóstico , Feminino , Neoplasias Oculares/veterinária , Neoplasias Oculares/patologia , Neoplasias Oculares/diagnóstico , Linfoma de Células B/veterinária , Linfoma de Células B/patologia , Linfoma de Células B/diagnósticoRESUMO
Polatuzumab vedotin, an antibody-drug conjugate targeting CD79B, is the first new drug approved for first-line therapy of diffuse large B-cell lymphoma in more than two decades, although factors determining treatment responses to polatuzumab vedotin remain unknown. Two new studies identified central mechanisms of lower sensitivity, namely reduced accessibility of the CD79B epitope through N-linked glycosylation of CD79B and lower CD79B surface expression levels due to the activity of the KLHL6 E3 ligase. See related article by Corcoran et al., p. 1653 (6) See related article by Meriranta et al. (7).
Assuntos
Imunoconjugados , Humanos , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Antígenos CD79 , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológicoRESUMO
BACKGROUND: Patients treated with anti-CD20 monoclonal antibodies could have a higher risk of adverse outcomes of coronavirus disease 2019 (COVID-19). The novel anti-CD20 monoclonal antibody obinutuzumab has shown greater B-cell depletion and superior in vitro efficacy than rituximab. We aimed to assess whether obinutuzumab would result in worse COVID-19 outcomes than rituximab. METHODS: We retrospectively reviewed 124 patients with B-cell lymphoma, 106 of whom received rituximab treatment and 18 of whom received obinutuzumab treatment. The adverse outcomes of COVID-19 were compared between patients in the two cohorts. RESULTS: The proportions of patients who were hospitalized (55.6% vs. 20.8%, p = 0.005), experienced prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (38.9% vs. 2.9%, p < 0.001), and developed severe COVID-19 (33.3% vs. 4.7%, p < 0.001) were higher in patients with obinutuzumab than in those with rituximab. Multivariate analyses showed that obinuzumab treatment was associated with higher incidences of prolonged SARS-CoV-2 infection (OR 27.05, 95% CI 3.75-195.22, p = 0.001) and severe COVID-19(OR 15.07, 95% CI 2.58-91.72, p = 0.003). CONCLUSIONS: Our study suggested that patients treated with obinutuzumab had a higher risk of prolonged SARS-CoV-2 infection and severe COVID-19 than those treated with rituximab.
Assuntos
Anticorpos Monoclonais Humanizados , COVID-19 , Rituximab , SARS-CoV-2 , Humanos , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , SARS-CoV-2/efeitos dos fármacos , Tratamento Farmacológico da COVID-19 , Resultado do Tratamento , Adulto , Linfoma de Células B/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Idoso de 80 Anos ou maisAssuntos
Antineoplásicos Imunológicos , Imunoterapia Adotiva , Linfoma de Células B , Linfoma de Células T , Segunda Neoplasia Primária , Humanos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Síndrome da Liberação de Citocina/imunologia , Herpesvirus Humano 4/isolamento & purificação , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfoma de Células B/virologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/imunologia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/imunologia , Receptores de Antígenos Quiméricos/imunologia , RiscoAssuntos
Antineoplásicos Imunológicos , Hematopoiese Clonal , Imunoterapia Adotiva , Linfoma de Células B , Linfoma de Células T , Segunda Neoplasia Primária , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/imunologia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/imunologia , Receptores de Antígenos Quiméricos/imunologia , Risco , Hematopoiese Clonal/genética , Hematopoiese Clonal/imunologia , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfoma de Células B/virologia , Herpesvirus Humano 4/isolamento & purificação , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/imunologiaRESUMO
BACKGROUND: Dexamethasone (Dex), a synthetic glucocorticoid that acts by binding to the glucocorticoid receptor (GR), has been widely applied to treat leukemia and lymphoma; however, the precise mechanism underlying Dex action is still not well elucidated. DOT1L, a histone H3-lysine79 (H3K79) methyltransferase, has been linked to multiple cancer types, particularly mixed lineage leukemia (MLL) gene rearranged leukemia, but its contribution to lymphoma is yet to be delineated. Analysis from the TCGA database displayed that DOT1L was highly expressed in lymphoma and leukemia. RESULTS: We initially demonstrated that DOT1L served as a new target gene controlled by GR, and the downregulation of DOT1L was critical for the killing of B-lymphoma cells by Dex. Further study revealed that Dex had no impact on the transcriptional activity of the DOT1L promoter, rather it reduced the mRNA level of DOT1L at the posttranscriptional level. In addition, knockdown of DOT1L remarkably inhibited the B-lymphoma cell growth. CONCLUSIONS: Overall, our findings indicated that DOT1L may serve as a potential drug target and a promising biomarker of Dex sensitivity when it comes to treating B lymphoma.
Assuntos
Proliferação de Células , Dexametasona , Histona-Lisina N-Metiltransferase , Linfoma de Células B , Metiltransferases , Receptores de Glucocorticoides , Humanos , Dexametasona/farmacologia , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Linfoma de Células B/genética , Metiltransferases/metabolismo , Metiltransferases/genética , Metiltransferases/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacosRESUMO
BACKGROUND: Chimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy. METHODS: We conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes. RESULTS: All patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46% of the patients. CAR-T therapy was associated with a higher incidence of biphasic, late-onset, or prolonged cytopenias. Survival analysis indicated that neutropenia and lymphopenia tended to be associated with better prognosis, whereas thrombocytopenia tended to be related to poorer outcomes. Through animal experiments, we discovered that MSCs infusion boosted HSCs and their long-term subpopulations, enhancing hematopoietic recovery, particularly in the megakaryocyte lineage, and mitigating bone marrow damage. Importantly, both in vitro and in vivo experiments demonstrated that MSCs did not compromise the activity or antitumor efficacy of CAR-T cells. CONCLUSIONS: Our findings propose MSCs infusion as a promising strategy to address cytopenias, particularly thrombocytopenia, after CAR-T therapy. This approach could help overcome certain limitations of cellular immunotherapy by enhancing hematopoietic recovery without compromising the efficacy of CAR-T cells. HIGHLIGHTS: 1 Cytopenia is a frequently observed adverse effect following CAR-T therapy, and it is often characterized by biphasic and prolonged patterns. 2 MSCs play a critical role in promoting hematopoietic recovery and mitigating bone marrow damage in a murine model of CAR-T therapy 3 The activity and antitumor efficacy of CAR-T cells were not impaired by MSCs.
Assuntos
Imunoterapia Adotiva , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Receptores de Antígenos Quiméricos , Animais , Humanos , Camundongos , Masculino , Feminino , Pessoa de Meia-Idade , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Adulto , Transplante de Células-Tronco Mesenquimais/métodos , Receptores de Antígenos Quiméricos/metabolismo , Idoso , Estudos Retrospectivos , Trombocitopenia/terapia , Hematopoese , Linfoma de Células B/terapia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Neutropenia/terapia , CitopeniaRESUMO
Bruton's tyrosine kinase (BTK) inhibitors are important therapeutic advances with promising efficacy outcomes in the treatment of patients with chronic lymphocytic leukemia and other B-cell lymphoma subtypes. However, the utility of BTK inhibitors can be limited by adverse events such as infections. In this systematic review and meta-analysis, we aim to determine the risk of various infections associated with BTK inhibitor monotherapy in B-cell lymphoma patients. A comprehensive search was conducted in MEDLINE/PubMed, Embase, and Web of Science databases from their inception until October 2023. ClinicalTrials.gov, bibliographies, and relevant conference abstracts were also searched for additional records. Randomized controlled trials that included any B-cell lymphoma patients treated with BTK inhibitor monotherapy and reported infection were included. Meta-analysis was performed to calculate risk ratio (RR) using a random-effects model in R Statistical Software, version 4.3.2. Of 3292 studies retrieved, we included 12 studies in this systematic review and meta-analysis. The median age of patients across the study arms ranged between 64 and 73 years. The overall pooled RR for any grade upper respiratory tract infections (URTI) associated with BTK inhibitor treatment was 1.55 (95% Confidence Interval (CI) 1.22-1.97). The RR of grade ≥3 URTI was reported in 14 out of 1046 patients, yielding an RR of 1.46 (95% CI 0.61-3.54), which was not statistically significant. The pooled RR of any grade pneumonia was 1.20 (95% CI 0.68-2.10) and grade ≥3 pneumonia was 1.12 (95% CI 0.67-1.85), both of which were not statistically significant. Patients with B-cell lymphoma who are undergoing BTK inhibitor monotherapy face an elevated risk of developing URTI. Clinicians prescribing BTK inhibitors should be aware of the potential infectious events that may occur. Close monitoring and the implementation of effective prophylactic measures are essential for managing these patients.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Linfoma de Células B , Inibidores de Proteínas Quinases , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Infecções/etiologia , Infecções/induzido quimicamente , Infecções/epidemiologia , Idoso , Pessoa de Meia-IdadeRESUMO
B-cell lymphoma, clinically, comprises a heterogeneous group of malignancies that encompass various subtypes. CD20 is an optimal target for therapeutic antibodies in B-cell lymphoma immunotherapy since approximately 90% of B-cell malignancies typically exhibit CD20 expression on their surface, while its presence is limited in normal tissues. In this study, we have developed a series of novel non-IgG-like T cell-dependent bispecific antibodies by constructing Fab-FabCH3, referred to as Tandem Antigen-binding Fragment 002 (TFAB002), which specifically target CD20 for the treatment of malignant B-cell lymphoma. TFAB002s display strong binding affinity with CD20 and moderate binding affinity with CD3, thereby triggering target-specific T-cell activation, cytokine release, and tumor cell lysis in vitro. Furthermore, TFAB002s exhibit potent cytotoxicity against B-cell malignancies that express varying levels of CD20. Besides, the TFAB002s show potent pharmacodynamic activity in vivo in the WIL2-S cells CDX mouse model. Collectively, these results underscore the potential of TFAB002s as a highly promising therapeutic approach for selectively depleting CD20-positive B cells, thereby warranting further clinical evaluation as a viable treatment option for CD20-expressing B-cell malignancies.
Assuntos
Anticorpos Biespecíficos , Antígenos CD20 , Fragmentos Fab das Imunoglobulinas , Linfoma de Células B , Linfócitos T , Animais , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/imunologia , Antígenos CD20/imunologia , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfoma de Células B/tratamento farmacológico , Camundongos , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Linfócitos T/imunologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Ativação Linfocitária/imunologia , Ativação Linfocitária/efeitos dos fármacos , FemininoRESUMO
BACKGROUND/OBJECTIVES: Systemic lupus erythematosus (lupus) and B-cell lymphoma (lymphoma) co-occur at higher-than-expected rates and primarily depend on B cells for their pathology. These observations implicate shared inflammation-related B cell molecular mechanisms as a potential cause of co-occurrence. METHODS: We consequently implemented a novel Immune Imbalance Transcriptomics (IIT) algorithm and applied IIT to lupus, lymphoma, and healthy B cell RNA-sequencing (RNA-seq) data to find shared and contrasting mechanisms that are potential therapeutic targets. RESULTS: We observed 7143 significantly dysregulated genes in both lupus and lymphoma. Of those genes, we found 5137 to have a significant immune imbalance, defined as a significant dysregulation by both diseases, as analyzed by IIT. Gene Ontology (GO) term and pathway enrichment of the IIT genes yielded immune-related "Neutrophil Degranulation" and "Adaptive Immune System", which validates that the IIT algorithm isolates biologically relevant genes in immunity and inflammation. We found that 344 IIT gene products are known targets for established and/or repurposed drugs. Among our results, we found 48 known and 296 novel lupus targets, along with 151 known and 193 novel lymphoma targets. Known disease drug targets in our IIT results further validate that IIT isolates genes with disease-relevant mechanisms. CONCLUSIONS: We anticipate the IIT algorithm, together with the shared and contrasting gene mechanisms uncovered here, will contribute to the development of immune-related therapeutic options for lupus and lymphoma patients.
Assuntos
Algoritmos , Lúpus Eritematoso Sistêmico , Linfoma de Células B , Transcriptoma , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Transcriptoma/genética , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/tratamento farmacológico , Linfócitos B/imunologia , Linfócitos B/metabolismo , Perfilação da Expressão Gênica/métodosRESUMO
RATIONALE: Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy is a successful treatment for B-cell malignancies associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cardiovascular toxicities have also been reported in this setting. However, there is scarce data regarding development of autonomic disorders after CAR-T cell therapy. PATIENT CONCERNS: We report a case with a patient with non-Hodgkin B-cell lymphoma, refractory to 2 prior lines of immunochemotherapy, treated with CAR-T therapy. DIAGNOSES: Orthostatic hypotension secondary to autonomic dysfunction was diagnosed as manifestation of ICANS. INTERVENTIONS: The patient received metilprednisolone 1000 mg IV daily for 3 days and anakinra 100 mg IV every 6h. OUTCOMES: The vast majority of autonomic symptoms ceased and 4 months after CAR-T therapy, autonomic dysfunction was resolved. LESSONS: New-onset autonomic dysfunction can occur as manifestation of ICANS in patients who experience persistent neurologic and cardiovascular symptoms after resolution of acute neurotoxicity and should be early recognized. Differences in differential diagnosis, mechanisms and treatment approaches are discussed.
Assuntos
Doenças do Sistema Nervoso Autônomo , Humanos , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Imunoterapia Adotiva/efeitos adversos , Masculino , Síndrome da Liberação de Citocina/etiologia , Pessoa de Meia-Idade , Linfoma de Células B/complicações , Linfoma de Células B/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/diagnóstico , Hipotensão Ortostática/etiologia , Hipotensão Ortostática/diagnóstico , Metilprednisolona/uso terapêuticoRESUMO
The Trp53 gene encodes several isoforms of elusive biological significance. Here, we show that mice lacking the Trp53 alternatively spliced (AS) exon, thereby expressing the canonical p53 protein but not isoforms with the AS C-terminus, have unexpectedly lost a male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in Trp53+/+Eµ-Myc males compared to Trp53ΔAS/ΔAS Eµ-Myc males, but also compared to Trp53+/+Eµ-Myc and Trp53ΔAS/ΔAS Eµ-Myc females. Pre-tumoral splenic cells from Trp53+/+Eµ-Myc males exhibited a higher expression of Ackr4, encoding an atypical chemokine receptor with tumor suppressive effects. We identified Ackr4 as a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine Eµ-Myc-induced and human Burkitt lymphomas. Furthermore, the knockout of ACKR4 increased the chemokine-guided migration of Burkitt lymphoma cells. These data demonstrate the functional relevance of alternatively spliced p53 isoforms and reveal sex disparities in Myc-driven lymphomagenesis.
Human cells divide many times during a lifetime, a process that requires careful regulation to avoid uncontrolled cell division, which can lead to various disorders, including cancer. For example, TP53, which encodes multiple proteins, is the most commonly mutated gene in cancers. TP53 carries the instructions to make a tumor suppressor protein, known as p53, which can stop cancers from forming and spreading. In humans and mice, TP53 (and the mouse analogue Trp53) can also be read by the cell to make several slightly different versions of the p53 protein, known as isoforms. The p53 isoforms are much less studied and their role in an organism is still unclear. To address this, Fajac et al. used genome editing to make mouse strains that were still able to express p53, but were only able to create a specific subset of p53 isoforms. In these mice, part of the Trp53 gene had been mutated to remove the cell's ability to make isoforms with an alternative C-terminal end. Fajac et al. then allowed these mice to breed with mice that were model organisms for a cancer called B-cell lymphoma. This revealed that male offspring that lacked alternative p53 isoforms were more susceptible to B-cell lymphoma and that they had decreased levels of the protein ACKR4, a receptor for signaling proteins that regulate cellular movement. Human datasets showed that having higher levels of ACKR4 could be linked to a better disease prognosis in male patients with Burkitt lymphoma, a rare but aggressive form of B-cell lymphoma. The same effect was not observed in females, suggesting that measuring ACKR4 gene expression in male patients with Burkitt lymphoma might be useful to identify the patients at higher risk. The study from Fajac et al. provides a new perspective on p53 one of the most studied proteins. It highlights specific p53 isoforms and the ACKR4 protein as a potential way to identify male patients at higher risk from a type of B-cell lymphoma.
Assuntos
Processamento Alternativo , Isoformas de Proteínas , Proteína Supressora de Tumor p53 , Animais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Camundongos , Masculino , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Feminino , Linfoma de Células B/genética , Prognóstico , Humanos , Fatores Sexuais , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
The t(14;19)(q32;q13) is a rare recurring translocation found in B-cell lymphoproliferative malignancies, involving the Bcl-3 gene. This chromosomal translocation is often found in patients under the age of 50 and causes a more progressive disease. The Bcl-3 gene encodes a protein belonging to the IκB family of proteins, which tightly regulates NFκB signaling by acting as an activator or repressor of transcription. Previously, we developed a second-generation Bcl-3 inhibitor that could directly interfere with Bcl-3 signaling pathway, resulting in reduced melanoma cell proliferation, invasion, and migration. The present study aimed to investigate the effect of a Bcl-3 inhibitor on B-cell lymphoma and leukemia cells. It was found that treatment of cells with this inhibitor caused a decrease in cell proliferation and cell survival. Furthermore, Bcl-3 inhibition in B-cell malignant cells resulted in the loss of mitochondrial membrane potential and functionality, as well as the increased expression of cleaved caspase 3, indicating that cell death occurs through the intrinsic apoptotic pathway. This observation is further supported by reduced expression of cIAP1 protein 1 (cIAP1) upon treatment of cancer cells. Given the current lack of clinical advancements targeting Bcl-3 in oncology, this opens a novel avenue for the development and investigation of highly specific therapeutic interventions against B-cell malignancies.
Assuntos
Apoptose , Proteína 3 do Linfoma de Células B , Proliferação de Células , Humanos , Proteína 3 do Linfoma de Células B/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma de Células B/metabolismo , Linfoma de Células B/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Caspase 3/metabolismoRESUMO
Assessing the prognosis of patients with aggressive non-Hodgkin B cell lymphoma mainly relies on a clinical risk score (IPI). Standard first-line therapies are based on a chemo-immunotherapy with rituximab, which mediates CD16-dependent antibody-dependent cellular cytotoxicity (ADCC). We phenotypically and functionally analyzed blood samples from 46 patients focusing on CD16+ NK cells, CD16+ T cells and CD16+ monocytes. Kaplan-Meier survival curves show a superior progression-free survival (PFS) for patients having more than 1.6% CD16+ T cells (p = 0.02; HR = 0.13 (0.007-0.67)) but an inferior PFS having more than 10.0% CD16+ monocytes (p = 0.0003; HR = 16.0 (3.1-291.9)) at diagnosis. Surprisingly, no correlation with NK cells was found. The increased risk of relapse in the presence of > 10.0% CD16+ monocytes is reversed by the simultaneous occurrence of > 1.6% CD16+ T cells. The unexpectedly strong protective function of CD16+ T cells could be explained by their high antibody-dependent cellular cytotoxicity as quantified by real-time killing assays and single-cell imaging. The combined analysis of CD16+ monocytes (> 10%) and CD16+ T cells (< 1.6%) provided a strong model with a Harrell's C index of 0.80 and a very strong power of 0.996 even with our sample size of 46 patients. CD16 assessment in the initial blood analysis is thus a precise marker for early relapse prediction.
Assuntos
Células Matadoras Naturais , Receptores de IgG , Humanos , Receptores de IgG/metabolismo , Prognóstico , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/imunologia , Monócitos/metabolismo , Monócitos/imunologia , Biomarcadores Tumorais , Masculino , Feminino , Recidiva Local de Neoplasia/patologia , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/sangue , Linfoma de Células B/metabolismo , Linfoma de Células B/sangue , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Linfócitos T/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Idoso , Estimativa de Kaplan-MeierRESUMO
INTRODUCTION: Crocin and Crocetin are compounds that have shown promising therapeutic potentials in various medical contexts. To date, the effect of crocin and crocetin on the expression level of miRNA-16-1 in Epstein Barr Virus (EBV)-induced lymphoma has not been investigated. This research delved into a comparative analysis of the cytotoxic effects of crocin and crocetin compared to cyclophosphamide, the main drug used in the treatment of lymphoma and PTLD, on B-cell lymphoma infected with EBV (cell line CO 88BV59-1). Additionally, the study examines the changes in miRNA-16-1 expression following these treatments in this cell line. MATERIALS AND METHODS: CO 88BV59-1 LCL cells were treated with crocin, crocetin (0.2 to 200 µM), and cyclophosphamide (0.05 to 50 µM) for 72 hours. Cell viability and apoptosis were assessed using resazurin and Annexin V/PI techniques, respectively. Additionally, the expression of miRNA-16-1-3p and miRNA-16-1-5p was determined using the Real-Time PCR method. The data were analyzed using one-way analysis of variance (ANOVA) with Tukey's multiple comparisons post-hoc test. RESULTS: Crocin and crocetin inhibited the proliferation and apoptosis caused by EBV-infected cells in a dose- and time-dependent manner (P<0.05). The expression levels of miRNA-16-1-3p and miRNA-16-1-5p remained unchanged in cells treated with crocin and crocetin. CONCLUSION: The study found that the cytotoxic effect of Crocin, Crocetin, and Cyclophosphamide on CO 88BV59-1 LCL is independent of the expression level of miRNA-16-1. The results showed a reduction in cell survival and an increase in cell death.
Assuntos
Apoptose , Carotenoides , Ciclofosfamida , Herpesvirus Humano 4 , MicroRNAs , Vitamina A , MicroRNAs/genética , Carotenoides/farmacologia , Humanos , Vitamina A/análogos & derivados , Vitamina A/farmacologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/efeitos dos fármacos , Ciclofosfamida/farmacologia , Apoptose/efeitos dos fármacos , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/virologia , Linfócitos B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/virologia , Linfoma de Células B/patologia , Transformação Celular Viral , Células Tumorais CultivadasRESUMO
Background Primary cutaneous lymphomas (PCLs) are rare diagnoses in Nepal and are not well characterized till date. Objective To evaluate clinical and pathological features of Primary cutaneous lymphomas in Nepal. Method We retrospectively reviewed outpatient and inpatient records of a dermatology referral centre of Kathmandu, Nepal for clinical and pathological findings of cases diagnosed as cutaneous lymphomas from July 2010 through July 2020. The final diagnosis was made based on 2008 World Health Organization classification and its update 2018. Result There were 12 cases of Primary cutaneous lymphomas diagnosed during this period. The age of presentation ranged from 19 years to 81 years (Mean: 53.4 years ± 21.5 years, SD). There were ten cases of cutaneous T-cell lymphoma (CTCLs) and two cases of cutaneous B- cell lymphomas (CBCLs). Among cutaneous T-cell lymphoma, there were four cases of primary cutaneous anaplastic large- cell Lymphoma (PCALCL), two cases of classic (patch/plaque) mycosis fungoides (MF), two cases of folliculotropic mycosis fungoides (FMF), and one case each of primary cutaneous aggressive epidermotropicCD8+ T-cell lymphoma and lymphomatoid papulosis. Among cutaneous B- cell lymphomas, there was one case of primary cutaneous marginal zone B- cell lymphoma, and one case of primary cutaneous follicle centre lymphoma. Most cases of MF presented at stage IB (75%), and three patients of primary cutaneous lymphomas died during this period. Conclusion Primary cutaneous lymphomas appear to be very rare in this study and presentations ranged from classic Mycoses Fungoides to aggressive T-cell lymphomas. Cutaneous T-cell lymphomas appeared to be more common than cutaneous B- cell lymphomas in this study.
Assuntos
Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Nepal/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Masculino , Feminino , Adulto , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Linfoma Cutâneo de Células T/patologia , Linfoma Cutâneo de Células T/epidemiologia , Adulto Jovem , Estudos de Coortes , Linfoma de Células B/epidemiologia , Linfoma de Células B/patologia , Dermatologia , Micose Fungoide/patologia , Micose Fungoide/epidemiologiaRESUMO
The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclax and an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor and cooperates with the loss of KMT2D in lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several proapoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histone H3K4 demethylases restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. These results establish SETD1B as an epigenetic regulator of cell death and reveal a pharmacological strategy to augment Venetoclax sensitivity in lymphoma.
Assuntos
Apoptose , Histona-Lisina N-Metiltransferase , Mutação , Proteínas Proto-Oncogênicas c-bcl-2 , Animais , Humanos , Camundongos , Apoptose/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/farmacologiaRESUMO
BACKGROUND: Splenic cysts are uncommon and very rarely malignant therefore their treatment isn't standardized. In case of symptomatic cysts different surgical approaches have been suggested. Primary malignant lymphoma of the spleen comprises less than 1% of non-Hodgkin's lymphomas. To our knowledge, only 203 cases of splenic large B-cell lymphoma (LBCL) have been reported to date and only 2 of them were fibrin-associated splenic cysts. CASE PRESENTATION: 27-year-old model with a 19 × 13 cm splenic cyst without data of malignancy in the preliminary study and therefore treated with laparoscopic deroofing. After histological diagnosis of LBCL with a fibrin/EBV-associated splenic pseudocyst, the patient received 4 cycles of Rituximab and a laparoscopic splenectomy was performed due to resurgence of the pseudocyst. No evidence of malignancy has been found during follow up (EBV viral load every 3 months during the first year, PET-CT every 6 months during the first year and annual afterwards) performed after the splenectomy. DISCUSSION AND CONCLUSIONS: The value of tumor markers and radiology for diagnosis of splenic cysts is put into question. Only 60 cases of Fibrin-associated LBCL (FA-LBCL) have been described in the literature therefore there are no treatment guidelines for them even though surgery together with systemic treatment has been the prevalent route with good results in most cases.
Assuntos
Cistos , Esplenectomia , Esplenopatias , Neoplasias Esplênicas , Humanos , Esplenectomia/métodos , Adulto , Cistos/cirurgia , Cistos/patologia , Esplenopatias/cirurgia , Esplenopatias/patologia , Neoplasias Esplênicas/cirurgia , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/complicações , Masculino , Prognóstico , Laparoscopia/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/cirurgia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma de Células B/cirurgia , Linfoma de Células B/patologia , Linfoma de Células B/complicações , Linfoma de Células B/diagnóstico , Rituximab/administração & dosagem , Rituximab/uso terapêuticoRESUMO
BACKGROUND: Ocular adnexal B cell lymphoma is the most common orbital malignancy in adults. Large chromosomal translocations and alterations in cell-signaling pathways were frequently reported in lymphomas. Among the altered pathways, perturbations of NFκB signaling play a significant role in lymphomagenesis. Specifically, the MYD88 L265P mutation, an activator of NFκB signaling, is extensively studied in intraocular lymphoma but not at other sites. Therefore, this study aims to screen the MYD88 L265P mutation in Ocular adnexal B cell lymphoma tumors and assess its clinical significance. METHODS AND RESULTS: Our study of twenty Ocular adnexal B cell lymphoma tumor samples by Allele-Specific Polymerase Chain Reaction identified two samples positive for the MYD88 L265P mutation. Subsequent Sanger sequencing confirmed the presence of the heterozygous mutation in those two samples tested positive in Allele-Specific Polymerase Chain Reaction. A comprehensive review of MYD88 L265P mutation in Ocular adnexal B cell lymphoma revealed variable frequencies, ranging from 0 to 36%. The clinical, pathological, and prognostic features showed no differences between patients with and without the MYD88 L265P mutation. CONCLUSION: The present study indicates that the MYD88 L265P mutation is relatively infrequent in our cohort, underscoring the need for further validation in additional cohorts.
Assuntos
Neoplasias Oculares , Linfoma de Células B , Mutação , Fator 88 de Diferenciação Mieloide , Fator 88 de Diferenciação Mieloide/genética , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Linfoma de Células B/genética , Idoso , Neoplasias Oculares/genética , Mutação/genética , Adulto , Alelos , Idoso de 80 Anos ou maisRESUMO
MYD88 p.L265P mutation occurs in over 90% of Waldenström's macroglobulinemia (WM), which is characterized by lymphoplasmacytic lymphoma (LPL) with monoclonal IgM. WM requires careful diagnosis due to overlapping features with other B-cell malignancies. Bing-Neel syndrome (BNS), a rare complication of WM, involves central nervous system (CNS) invasion. This report describes two cases of morphologically low-grade B-cell lymphoma in the bone marrow accompanied by the presence of a large B-cell lymphoma in the brain and a common MYD88 p.L265P mutation, which were eventually established as BNS mimickers. Although the two components in these cases showed the same identical light-chain restriction, different immunoglobulin heavy-chain rearrangement peaks indicated distinct lymphoma stem cells for CNS and bone marrow lesions. These clinical cases emphasize the challenges in diagnosing BNS. Based on the findings, biopsy is recommended for accurate identification of the clonal relationship and MYD88 mutation status.