RESUMEN
Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understood how the cells making them evade immune checkpoints. Here, single-cell multi-omics analysis demonstrates a shared mechanism with lymphoid malignancy in the formation of public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemic vasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptide sequencing and antibody synthesis, rare circulating B lymphocytes making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations. Lymphoma driver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)J mutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergo phase transition to insoluble aggregates at lower temperatures. These results reveal a pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutations leading to an iconic pathogenic autoantibody.
Asunto(s)
Autoanticuerpos/genética , Enfermedades Autoinmunes/genética , Linfocitos B/inmunología , Linfoma/genética , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Linfocitos B/patología , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Portadoras/genética , Evolución Clonal/genética , Evolución Clonal/inmunología , Ciclina D3/genética , Guanilato Ciclasa/genética , Humanos , Proteínas Inmediatas-Precoces/genética , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Proteínas Inhibidoras de la Diferenciación/genética , Linfoma/inmunología , Linfoma/patología , Ratones , Mutación/genética , Mutación/inmunología , Proteínas de Neoplasias/genética , Análisis de Secuencia de ADN/métodos , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteínas Supresoras de Tumor/genética , Recombinación V(D)J/genéticaRESUMEN
PI3Ks are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids, which directly activate signal transduction pathways. In addition to being frequently genetically activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder that predisposes to lymphoma. The class II and class III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an often indirect effect on cell signalling. Here, we summarize current knowledge of the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are activated. Deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes and, ultimately, of human disease.
Asunto(s)
Endosomas/metabolismo , Linfoma/enzimología , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Animales , Transporte Biológico Activo , Endocitosis , Humanos , Isoenzimas/metabolismo , Linfoma/patologíaRESUMEN
B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach.
Asunto(s)
Modelos Animales de Enfermedad , Herpesvirus Humano 4 , Vigilancia Inmunológica , Linfoma/inmunología , Linfoma/terapia , Proteínas de la Matriz Viral/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Humanos , Inmunoterapia , Linfoma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Proteínas de la Matriz Viral/genéticaRESUMEN
DNA Ligase IV is responsible for sealing of double-strand breaks (DSBs) during nonhomologous end-joining (NHEJ). Inhibiting Ligase IV could result in amassing of DSBs, thereby serving as a strategy toward treatment of cancer. Here, we identify a molecule, SCR7 that inhibits joining of DSBs in cell-free repair system. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding but not that of T4 DNA Ligase or Ligase I. SCR7 inhibits NHEJ in a Ligase IV-dependent manner within cells, and activates the intrinsic apoptotic pathway. More importantly, SCR7 impedes tumor progression in mouse models and when coadministered with DSB-inducing therapeutic modalities enhances their sensitivity significantly. This inhibitor to target NHEJ offers a strategy toward the treatment of cancer and improvement of existing regimens.
Asunto(s)
Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , ADN Ligasas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pirimidinas/uso terapéutico , Bases de Schiff/uso terapéutico , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , ADN Ligasa (ATP) , ADN Ligasas/química , ADN Ligasas/genética , Modelos Animales de Enfermedad , Diseño de Fármacos , Resistencia a Antineoplásicos , Humanos , Linfocitos/efectos de los fármacos , Linfoma/tratamiento farmacológico , Linfoma/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Pirimidinas/síntesis química , Pirimidinas/química , Tolerancia a Radiación , Ratas , Bases de Schiff/síntesis química , Bases de Schiff/química , Alineación de SecuenciaRESUMEN
Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction1, although their biological functions are poorly understood. Mutations in the genes that encode H1 isoforms B-E (H1B, H1C, H1D and H1E; also known as H1-5, H1-2, H1-3 and H1-4, respectively) are highly recurrent in B cell lymphomas, but the pathogenic relevance of these mutations to cancer and the mechanisms that are involved are unknown. Here we show that lymphoma-associated H1 alleles are genetic driver mutations in lymphomas. Disruption of H1 function results in a profound architectural remodelling of the genome, which is characterized by large-scale yet focal shifts of chromatin from a compacted to a relaxed state. This decompaction drives distinct changes in epigenetic states, primarily owing to a gain of histone H3 dimethylation at lysine 36 (H3K36me2) and/or loss of repressive H3 trimethylation at lysine 27 (H3K27me3). These changes unlock the expression of stem cell genes that are normally silenced during early development. In mice, loss of H1c and H1e (also known as H1f2 and H1f4, respectively) conferred germinal centre B cells with enhanced fitness and self-renewal properties, ultimately leading to aggressive lymphomas with an increased repopulating potential. Collectively, our data indicate that H1 proteins are normally required to sequester early developmental genes into architecturally inaccessible genomic compartments. We also establish H1 as a bona fide tumour suppressor and show that mutations in H1 drive malignant transformation primarily through three-dimensional genome reorganization, which leads to epigenetic reprogramming and derepression of developmentally silenced genes.
Asunto(s)
Transformación Celular Neoplásica/genética , Cromatina/química , Cromatina/genética , Histonas/deficiencia , Histonas/genética , Linfoma/genética , Linfoma/patología , Alelos , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Autorrenovación de las Células , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina/genética , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Genes Supresores de Tumor , Centro Germinal/patología , Histonas/metabolismo , Humanos , Linfoma/metabolismo , Ratones , Mutación , Células Madre/metabolismo , Células Madre/patologíaRESUMEN
ABSTRACT: Although CD20×CD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in central nervous system (CNS) lymphoma is unknown. Here, we report the CD20×CD3 bispecific glofitamab penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces clinical responses in patients with secondary CNS.
Asunto(s)
Anticuerpos Biespecíficos , Neoplasias del Sistema Nervioso Central , Humanos , Neoplasias del Sistema Nervioso Central/inmunología , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Anticuerpos Biespecíficos/uso terapéutico , Barrera Hematoencefálica/patología , Antígenos CD20/inmunología , Complejo CD3/inmunología , Femenino , Masculino , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Linfoma de Células B/tratamiento farmacológico , Linfoma/inmunología , Linfoma/patología , Linfoma/tratamiento farmacológico , Persona de Mediana EdadRESUMEN
ABSTRACT: Rituximab (RTX) and other monoclonal antibodies (mAbs) that bind directly to malignant cells are of great clinical value but are not effective for all patients. A major mechanism of action of RTX is antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells. Prior in vitro studies in our laboratory demonstrated that T cells contribute to maintaining the viability and cytotoxic potential of NK cells activated by anti-CD20-coated target B cells. Here, we conducted studies using a novel mouse model and clinical correlative analysis to assess whether T-cell help contribute to RTX-mediated NK-cell ADCC in the tumor microenvironment (TME) in vivo. A humanized mouse model was developed using Raji lymphoma cells and normal donor peripheral blood mononuclear cells that allows for control of T-cell numbers in the lymphoma TME. In this model, NK-cell viability and CD16 and CD25 expression dropped after RTX in the absence of T cells but increased in the presence of T cells. RTX therapy was more effective when T cells were present and was ineffective when NK cells were depleted. In patients with indolent lymphoma, fine needle aspirates were obtained before and â¼1 week after treatment with a RTX-containing regimen. There was a strong correlation between CD4+ T cells as well as total T cells in the pretherapy TME and an increase in NK-cell CD16 and CD25 expression after RTX. We conclude that T-cell help in the TME enhances RTX-mediated NK-cell viability and ADCC.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Células Asesinas Naturales , Rituximab , Microambiente Tumoral , Rituximab/farmacología , Rituximab/uso terapéutico , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Animales , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Humanos , Ratones , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Línea Celular Tumoral , Ratones SCID , Linfoma/inmunología , Linfoma/tratamiento farmacológico , Linfoma/patología , Linfoma/terapia , FemeninoRESUMEN
Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma and various autoimmune disorders. Here we identified a signaling pathway that was exclusively responsible for the production of inflammatory cytokines but not for cytotoxicity. Recognition of tumor cells expressing the NK cell-activatory ligands H60 or CD137L by mouse natural killer (NK) cells led to efficient cytotoxicity and the production of inflammatory cytokines. Both of those effector functions required the kinases Lck, Fyn and PI(3)K (subunits p85α and p110δ) and the signaling protein PLC-γ2. However, a complex of Fyn and the adaptor ADAP exclusively regulated the production of inflammatory cytokines but not cytotoxicity in NK cells. That unique function of ADAP required a Carma1-Bcl-10-MAP3K7 signaling axis. Our results have identified molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Proteínas Adaptadoras de Señalización CARD/inmunología , Citocinas/biosíntesis , Células Asesinas Naturales/inmunología , Quinasas Quinasa Quinasa PAM/inmunología , Proteínas Proto-Oncogénicas c-fyn/inmunología , Transducción de Señal/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteína 10 de la LLC-Linfoma de Células B , Proteínas Adaptadoras de Señalización CARD/genética , Línea Celular Tumoral , Técnicas de Cocultivo , Citocinas/inmunología , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Inflamación , Células Asesinas Naturales/patología , Linfoma/genética , Linfoma/inmunología , Linfoma/patología , Quinasas Quinasa Quinasa PAM/genética , Ratones , Proteínas Proto-Oncogénicas c-fyn/genéticaRESUMEN
The study was conducted to assess the feasibility of integrating state-of-the-art sequencing techniques and flow cytometry into diagnostic workup of pediatric lymphoma. RNA sequencing (RNAseq), whole exome sequencing, and flow cytometry were implemented into routine diagnostic workup of pediatric biopsies with lymphoma in the differential diagnosis. Within 1 year, biopsies from 110 children (122 specimens) were analyzed because of suspected malignant lymphoma. The experience with a standardized workflow combining histology and immunohistochemistry, flow cytometry, and next-generation sequencing technologies is reported. Flow cytometry was performed with fresh tissue in 83% (102/122) of specimens and allowed rapid diagnosis of T-cell and B-cell non-Hodgkin lymphomas. RNAseq was performed in all non-Hodgkin lymphoma biopsies and 42% (19/45) of Hodgkin lymphoma samples. RNAseq detected all but one of the translocations found by fluorescence in situ hybridization and PCR. RNAseq and whole exome sequencing identified additional genetic abnormalities not detected by conventional approaches. Finally, 3 cases are highlighted to exemplify how synergy between different diagnostic techniques and specialists can be achieved. This study demonstrates the feasibility and discusses the added value of integrating modern sequencing techniques and flow cytometry into a workflow for routine diagnostic workup of lymphoma. The inclusion of RNA and DNA sequencing not only supports diagnostics but also will lay the ground for the development of novel research-based treatment strategies for pediatric lymphoma patients.
Asunto(s)
Linfoma , Humanos , Niño , Secuenciación del Exoma , Citometría de Flujo/métodos , Hibridación Fluorescente in Situ , Linfoma/patología , Análisis de Secuencia de ARN , ARNRESUMEN
Primary gastrointestinal (GI) T-cell and natural killer (NK)-cell lymphomas/lymphoproliferative disorders (LPD) are uncommon, and they are usually aggressive in nature. However, T-cell and NK-cell lymphoma/LPD of the GI tract with indolent clinical course has been reported over the past 2 decades. Indolent T-cell LPD was formally proposed a decade ago in 2013 and 4 years later recognized as a provisional entity by the revised fourth edition of WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues in 2017. Indolent T-cell LPD of the GI tract has been changed to indolent T-cell lymphoma of the GI tract as a distinct entity by the fifth edition of WHO Classification of Haematolymphoid Tumours, but the International Consensus Classification of mature lymphoid neoplasms prefers indolent clonal T-cell LPD of the GI tract instead. In the past decade, indolent lymphoma/LPD of the GI tract has been expanded to NK cells, and as such, indolent NK-cell LPD of the GI tract was recognized as an entity by both the fifth edition of WHO Classification of Haematolymphoid Tumours and the International Consensus Classification. The underlying genetic/molecular mechanisms of both indolent T-cell lymphoma/LPD of the GI tract and indolent NK-cell LPD of the GI tract have been recently discovered. In this review, we describe the history; salient clinical, cytohistomorphologic, and immunohistochemical features; and genetic/genomic landscape of both entities. In addition, we also summarize the mimics and differential diagnosis. Finally, we propose future directions with regard to the pathogenesis and clinical management.
Asunto(s)
Linfoma de Células T , Linfoma , Trastornos Linfoproliferativos , Humanos , Linfoma/diagnóstico , Linfoma/patología , Tracto Gastrointestinal/patología , Células Asesinas Naturales , Linfoma de Células T/diagnóstico , Linfocitos T/patología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/patologíaRESUMEN
One fourth of colorectal cancer patients having curative surgery will relapse of which the majority will die. Lymph node (LN) metastasis is the single most important prognostic factor and a key factor when deciding on postoperative treatment. Presently, LN metastases are identified by histopathological examination, a subjective method analyzing only a small LN volume and giving no information on tumor aggressiveness. To better identify patients at risk of relapse we constructed a qRT-PCR test, ColoNode, that determines levels of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN mRNAs. Combined these biomarkers estimate the tumor cell load and aggressiveness allocating patients to risk categories with low (0, -1), medium (1), high (2) and very high (3) risk of recurrence. Here we present result of a prospective, national multicenter study including 196 colon cancer patients from 8 hospitals. On average, 21 LNs/patient, totally 4698 LNs, were examined by both histopathology and ColoNode. At 3-year follow-up, 36 patients had died from colon cancer or lived with recurrence. ColoNode identified all patients that were identified by histopathology and in addition 9 patients who were undetected by histopathology. Thus, 25% of the patients who recurred were identified by ColoNode only. Multivariate Cox regression analysis proved ColoNode (1, 2, 3 vs 0, -1) as a highly significant risk factor with HR 4.24 [95% confidence interval, 1.42-12.69, P = .01], while pTN-stage (III vs I/II) lost its univariate significance. In conclusion, ColoNode surpassed histopathology by identifying a significantly larger number of patients with future relapse and will be a valuable tool for decisions on postoperative treatment.
Asunto(s)
Neoplasias del Colon , Linfoma , Humanos , Ganglios Linfáticos/patología , Estudios Prospectivos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Metástasis Linfática/patología , Linfoma/patología , Recurrencia , Reacción en Cadena de la Polimerasa , Estadificación de Neoplasias , Escisión del Ganglio Linfático , Estudios Retrospectivos , Moléculas de Adhesión Celular/genéticaRESUMEN
Rev1 has two important functions in the translesion synthesis pathway, including dCMP transferase activity, and acts as a scaffolding protein for other polymerases involved in translesion synthesis. However, the role of Rev1 in mutagenesis and tumorigenesis in vivo remains unclear. We previously generated Rev1-overexpressing (Rev1-Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after N-methyl-N-nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU-induced TL tumorigenesis in wild-type (WT) and Rev1-Tg mice using diverse approaches, including whole-exome sequencing (WES). In Rev1-Tg TLs, the mutation frequency was higher than that in WT TL in most cases. However, no difference in the number of nonsynonymous mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) genes was observed, and mutations involved in Notch1 and MAPK signaling were similarly detected in both TLs. Mutational signature analysis of WT and Rev1-Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging-related) and SBS11 (alkylation-related). Interestingly, the total number of mutations, but not the genotypes of WT and Rev1-Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in Rev1-Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in Rev1-Tg mice than in WT mice, following MNU treatment. In conclusion, Rev1 overexpression accelerates mutagenesis and increases the incidence of MNU-induced TL by shortening the latency period, which may be associated with more frequent DNA damage-induced genetic instability.
Asunto(s)
ADN Polimerasa Dirigida por ADN , Metilnitrosourea , Mutagénesis , Nucleotidiltransferasas , Neoplasias del Timo , Animales , Ratones , ADN Polimerasa Dirigida por ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Secuenciación del Exoma , Linfoma/genética , Linfoma/inducido químicamente , Linfoma/patología , Metilnitrosourea/toxicidad , Ratones Transgénicos , Mutación , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Neoplasias del Timo/genética , Neoplasias del Timo/inducido químicamente , Neoplasias del Timo/patologíaRESUMEN
Flow cytometry (FC) incorporating the T-cell receptor ß constant chain-1 (TRBC1) has been recently proposed as a new standard in T-cell clonality assessment. While early studies demonstrated high sensitivity in samples with conspicuous tumour burden, performance in real-world samples, including those with low tumour burden and correlation with molecular methods has been limited. We evaluated TRBC1-FC performance and correlated the results with high-throughput TRB sequencing and a targeted next-generation sequencing gene panel. Our cohort consisted of 90 evaluable samples from 57 patients. TRBC1-FC confirmed T-cell clonality in 37 out of 38 samples (97%) that were involved in a mature T-cell neoplasm (MTCN). T-cell clonality was also identified in nine samples from patients lacking a current or prior diagnosis of MTCN, consistent with the emerging entity T-cell clonality of uncertain significance. TRBC-FC was polyclonal in all samples and negative for disease involvement by standard pathology assessment. However, correlation with TRB sequencing in 17 of these samples identified two cases that harboured the known clonal sequence from index testing, indicating the presence of measurable residual disease not otherwise detected. Our study provides real-world correlative validation of TRBC1-FC, highlighting the strengths and limitations pertinent to its increasing implementation by general diagnostic laboratories.
Asunto(s)
Linfoma , Linfocitos T , Humanos , Linfocitos T/patología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Citometría de Flujo/métodos , Receptores de Antígenos de Linfocitos T , Linfoma/patologíaRESUMEN
Primary testicular lymphoma (PTL) is a rare lymphoma predominantly occurring in the elderly male population. It is characterized by a limited response to treatment and a heightened tendency towards relapse. Histologically, approximately 90% of PTL cases are classified as diffuse large B-cell lymphomas (DLBCL). Genetic features of PTL were delineated in a limited scope within several independent studies. Some of the articles which analyzed the genetic characterization of DLBCL have incorporated PTL samples, but these have been constrained by small sample sizes. In addition, there have been an absence of independent molecular typing studies of PTL. This report summarizes the common mutational features, copy number variations (CNVs) and molecular typing of PTL patients, based on whole-exome sequencing (WES) conducted on a cohort of 25 PTL patients. Among them, HLA, CDKN2A and MYD88 had a high mutation frequency. In addition, we found two core mutational characteristics in PTL including mutation in genes linked to genomic instability (TP53 and CDKN2A) and mutation in immune-related genes (HLA, MYD88, CD79B). We performed molecular typing of 25 PTL patients into C1 subtype with predominantly TP53 mutations and C2 subtype with predominantly HLA mutations. Notably, mutations in the TP53 gene predicted a poor outcome in most types of lymphomas. However, the C1 subtype, dominated by TP53 mutations, had a better prognosis compared to the C2 subtype in PTL. C2 subtype exhibited a worse prognosis, aligning with our finding that the mechanism of immune escape in PTL was primarily the deletions of HLA rather than PD-L1/PD-L2 alterations, a contrast to other DLBCLs. Moreover, we calculated the tumor mutation burden (TMB) and identified that TMB can predict prognosis and recurrence rate in PTL. Our study underscores the significance of molecular typing in PTL based on mutational characteristics, which plays a crucial role in prognostication and guiding therapeutic strategies for patients.
Asunto(s)
Variaciones en el Número de Copia de ADN , Genómica , Mutación , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Neoplasias Testiculares/clasificación , Mutación/genética , Variaciones en el Número de Copia de ADN/genética , Anciano , Persona de Mediana Edad , Linfoma/genética , Linfoma/patología , Linfoma/clasificación , Secuenciación del Exoma , Anciano de 80 o más Años , Adulto , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/clasificaciónRESUMEN
After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cells or reenter the DZ. The molecular circuits that govern positive selection in the GC are not known. We show here that the GC reaction required biphasic regulation of expression of the cell-cycle regulator c-Myc that involved its transient induction during early GC commitment, its repression by Bcl-6 in DZ B cells and its reinduction in B cells selected for reentry into the DZ. Inhibition of c-Myc in vivo led to GC collapse, which indicated an essential role for c-Myc in GCs. Our results have implications for the mechanism of GC selection and the role of c-Myc in lymphomagenesis.
Asunto(s)
Linfocitos B/metabolismo , Genes myc/inmunología , Centro Germinal/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Ciclo Celular/genética , Ciclo Celular/inmunología , Movimiento Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Regulación de la Expresión Génica , Genes Reporteros , Centro Germinal/inmunología , Centro Germinal/patología , Proteínas Fluorescentes Verdes , Linfoma/genética , Linfoma/metabolismo , Linfoma/patología , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-bcl-6/inmunología , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
Germinal centers (GCs) are sites of intense B cell proliferation and are central for T cell-dependent antibody responses. However, the role of c-Myc, a key cell-cycle regulator, in this process has been questioned. Here we identified c-Myc(+) B cell subpopulations in immature and mature GCs and found, by genetic ablation of Myc, that they had indispensable roles in the formation and maintenance of GCs. The identification of these functionally critical cellular subsets has implications for human B cell lymphomagenesis, which originates mostly from GC B cells and frequently involves MYC chromosomal translocations. As these translocations are generally dependent on transcription of the recombining partner loci, the c-Myc(+) GC subpopulations may be at a particularly high risk for malignant transformation.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/metabolismo , Ciclo Celular/genética , Centro Germinal/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Ciclo Celular/inmunología , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Eliminación de Gen , Regulación de la Expresión Génica/inmunología , Genes Reporteros , Sitios Genéticos , Centro Germinal/inmunología , Centro Germinal/patología , Proteínas Fluorescentes Verdes , Linfoma/genética , Linfoma/metabolismo , Linfoma/patología , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-myc/deficiencia , Proteínas Proto-Oncogénicas c-myc/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología , Translocación GenéticaRESUMEN
Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.
Asunto(s)
Neoplasias Hematológicas , Linfoma , Comités Consultivos , Consenso , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos , Linfoma/patología , Organización Mundial de la SaludRESUMEN
Epidemiological data have provided limited and inconsistent evidence on the relationship between radiation exposure and lymphoid neoplasms. We classified 553 lymphoid neoplasm cases diagnosed between 1950 and 1994 in the Life Span Study cohort of atomic bomb survivors into World Health Organization subtypes. Mature B-cell neoplasms represented 58%, mature T-cell and natural killer (NK)-cell neoplasms 20%, precursor cell neoplasms 5%, and Hodgkin lymphoma (HL) 3%, with the remaining 15% classified as non-Hodgkin lymphoid (NHL) neoplasms or lymphoid neoplasms not otherwise specified. We used Poisson regression methods to assess the relationship between radiation exposure and the more common subtypes. As in earlier reports, a significant dose response for NHL neoplasms as a group was seen for males but not females. However, subtype analyses showed that radiation dose was strongly associated with increased precursor cell neoplasms rates, with an estimated excess relative risk per Gy of 16 (95% Confidence interval: 7.0, >533) at age 50. The current data based primarily of tissue-based diagnoses suggest that the association between radiation dose and lymphoid neoplasms as a group is largely driven by the radiation effect on precursor cell neoplasms while presenting no evidence of a radiation dose response for major categories of mature cell neoplasms, either B- or T-/NK-cell, or more specific disease entities (diffuse large B-cell lymphoma, plasma cell myeloma, adult T-cell leukemia/lymphoma) or HL.
Asunto(s)
Supervivientes a la Bomba Atómica , Leucemia Linfoide/etiología , Linfoma/etiología , Neoplasias Inducidas por Radiación/etiología , Adolescente , Adulto , Femenino , Humanos , Incidencia , Leucemia Linfoide/patología , Linfoma/patología , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/patología , Ceniza Radiactiva/efectos adversos , Riesgo , Organización Mundial de la Salud , Adulto JovenRESUMEN
According to expert guidelines, lymph node surgical excision is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has become widely accepted as part of the lymphoma diagnostic workup over the past decades. The aim of this study was to present the largest multicenter inventory of lymph nodes sampled either by CNB or surgical excision in patients with suspected lymphoma and to compare their diagnostic performance in routine pathologic practice. We reviewed 32 285 cases registered in the French Lymphopath network, which provides a systematic expert review of all lymphoma diagnoses in France, and evaluated the percentage of CNB and surgical excision cases accurately diagnosed according to the World Health Organization classification. Although CNB provided a definitive diagnosis in 92.3% and seemed to be a reliable method of investigation for most patients with suspected lymphoma, it remained less conclusive than surgical excision, which provided a definitive diagnosis in 98.1%. Discordance rates between referral and expert diagnoses were higher on CNB (23.1%) than on surgical excision (21.2%; P = .004), and referral pathologists provided more cases with unclassified lymphoma or equivocal lesion through CNB. In such cases, expert review improved the diagnostic workup by classifying â¼90% of cases, with higher efficacy on surgical excision (93.3%) than CNB (81.4%; P < 10-6). Moreover, diagnostic concordance for reactive lesions was higher on surgical excision than CNB (P = .009). Overall, although CNB accurately diagnoses lymphoma in most instances, it increases the risk of erroneous or nondefinitive conclusions. This large-scale survey also emphasizes the need for systematic expert review in cases of lymphoma suspicion, especially in those sampled by using CNB.
Asunto(s)
Neoplasias de la Mama , Linfoma , Humanos , Femenino , Biopsia con Aguja Gruesa/métodos , Linfoma/diagnóstico , Linfoma/cirugía , Linfoma/patología , Escisión del Ganglio Linfático , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Biopsia , Estudios Retrospectivos , Neoplasias de la Mama/patología , Estudios Multicéntricos como AsuntoRESUMEN
This article will review current aspects of the histopathological, immunohistochemical and molecular analysis of primary mediastinal germ cell tumours (PMGCTs) as well as their aetiological, epidemiological, clinical and therapeutic features. PMGCTs represent an important differential diagnosis in the spectrum of mediastinal tumours, and their diagnosis is usually made on small tissue samples from core needle biopsies in combination with diagnostic imaging and serum tumour markers. As in lymphomas, a small biopsy is often the only viable tumour sample available from these patients, as they receive chemotherapy prior to eventual surgical resection. Pathologists therefore need to apply an efficient combination of immunohistochemical markers to confirm the diagnosis of a PMGCT and to exclude morphological mimics.