RESUMEN
RNA-binding proteins of the ZFP36 family are best known for inhibiting the expression of cytokines through binding to AU-rich elements in the 3' untranslated region and promoting mRNA decay. Here we identified an indispensable role for ZFP36L1 as the regulator of a post-transcriptional hub that determined the identity of marginal-zone B cells by promoting their proper localization and survival. ZFP36L1 controlled a gene-expression program related to signaling, cell adhesion and locomotion; it achieved this in part by limiting expression of the transcription factors KLF2 and IRF8, which are known to enforce the follicular B cell phenotype. These mechanisms emphasize the importance of integrating transcriptional and post-transcriptional processes by RNA-binding proteins for maintaining cellular identity among closely related cell types.
Asunto(s)
Linfocitos B/inmunología , Adhesión Celular/genética , Movimiento Celular/genética , Proteínas Nucleares/genética , Proteínas de Unión al ARN/genética , Animales , Factor 1 de Respuesta al Butirato , Adhesión Celular/inmunología , Movimiento Celular/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Factores Reguladores del Interferón/genética , Factores de Transcripción de Tipo Kruppel/genética , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Ratones , Proteínas Nucleares/inmunología , Fenotipo , Proteínas de Unión al ARN/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ARN , Transducción de SeñalRESUMEN
DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.
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Linfocitos B/enzimología , ARN Helicasas DEAD-box/metabolismo , Linfoma de Células B/enzimología , Antígenos de Histocompatibilidad Menor/metabolismo , Proteínas de Neoplasias/biosíntesis , Proteínas Proto-Oncogénicas c-myc/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Linfocitos B/patología , Línea Celular Tumoral , Niño , Preescolar , ARN Helicasas DEAD-box/genética , Estrés del Retículo Endoplásmico , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación con Pérdida de Función , Linfoma de Células B/genética , Linfoma de Células B/patología , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor/genética , Proteínas de Neoplasias/genética , Biosíntesis de Proteínas , Proteoma , Proteostasis , Proteínas Proto-Oncogénicas c-myc/genética , Adulto JovenRESUMEN
The lymphocyte genome is prone to many threats, including programmed mutation during differentiation1, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.
Asunto(s)
Linfocitos , Mutación , Linfocitos B/citología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , Diferenciación Celular , Proliferación Celular , Microambiente Celular , Daño del ADN/genética , Daño del ADN/efectos de la radiación , Centro Germinal/citología , Centro Germinal/inmunología , Humanos , Memoria Inmunológica/genética , Linfocitos/citología , Linfocitos/inmunología , Linfocitos/metabolismo , Linfocitos/patología , Neoplasias/genética , Neoplasias/patologíaRESUMEN
Epstein-Barr virus (EBV) is an important cause of human lymphomas, including Burkitt lymphoma (BL). EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-κB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (ΔEBNA2 EBV) to create the first in vivo model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both ΔEBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L/IL21 expressing feeder layer in vitro and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.
Asunto(s)
Linfocitos B , Linfoma de Burkitt , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Proteínas Proto-Oncogénicas c-myc , Latencia del Virus , Animales , Linfoma de Burkitt/virología , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Linfoma de Burkitt/genética , Humanos , Ratones , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Linfocitos B/virología , Linfocitos B/metabolismo , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Antígenos Nucleares del Virus de Epstein-Barr/genética , Apoptosis , Proteínas Virales/metabolismo , Proteínas Virales/genéticaRESUMEN
Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/metabolismo , Glicina Hidroximetiltransferasa/antagonistas & inhibidores , Glicina Hidroximetiltransferasa/metabolismo , Animales , Linfoma de Burkitt/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Descubrimiento de Drogas , Formiatos/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Glicina/metabolismo , Glicina Hidroximetiltransferasa/genética , Humanos , Ratones , Terapia Molecular Dirigida , Proteolisis/efectos de los fármacosRESUMEN
With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.
Asunto(s)
Linfoma , Neoplasias , Humanos , Linfoma/diagnóstico , Linfoma/genética , Linfoma/terapia , Genómica/métodos , Medicina de Precisión , Secuenciación de Nucleótidos de Alto Rendimiento , Toma de Decisiones ClínicasRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma curable even in advanced stages. DLBCL involving the central nervous system (CNS) is more difficult to cure and fewer treatment options exist. Primary CNS lymphoma (PCNSL) refers to aggressive lymphomas confined to the CNS, and are almost always DLBCL. Standard approaches for PCNSL use high-dose methotrexate-based combinations as induction therapy and younger patients often receive dose-intensive consolidation. However, dose-intensive therapies are not suitable for all patients, and older patients have fewer effective treatment options. Patients with relapsed or chemotherapy-refractory disease have a very poor prognosis. Secondary CNS lymphoma (SCNSL) describes aggressive lymphomas involving the CNS at initial presentation or relapses within the CNS after treatment for systemic DLBCL. Isolated CNS relapse is often managed as PCNSL, but patients with synchronous involvement of DLBCL in both the periphery and the CNS pose a unique clinical challenge. Insights into the molecular circuitry of DLBCL have identified distinct genetic subtypes including cases with a predilection for CNS invasion. PCNSL and subsets of SCNSL are characterized by chronically activated B-cell receptor and NFκB signaling along with genetic evidence of immune evasion which may be exploited therapeutically. Improved mechanistic understanding of targetable pathways underpinning CNS lymphomas has led to numerous clinical trials testing targeted agent combinations and immunotherapy approaches with promising early results. Biologically rational strategies may further improve the cure rate of CNS lymphomas, either by overcoming intrinsic or acquired treatment resistance and/or by being broadly applicable to patients of all ages.
Asunto(s)
Productos Biológicos , Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistema Nervioso Central/patología , Productos Biológicos/uso terapéuticoRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Over the previous 2 decades, tremendous progress has been made in our understanding of the molecular pathogenesis of DLBCL. However, this biological understanding has not yet been translated into improved first-line therapy. A major barrier to the introduction of molecularly targeted therapy in DLBCL is the considerable molecular heterogeneity of this disease. Recent studies have tried to rationalize this heterogeneity by proposing new genetic subtypes of DLBCL. Although remarkable consensus exists over the broad nature of these genetic subtypes, important questions remain over precisely how, or even why, genetic subtyping might be incorporated into diagnostic laboratories. In this review, we compare the findings of the major genetic subtyping studies and discuss the implications this may have for diagnostic pathology services and the management of DLBCL.
Asunto(s)
Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/patología , Terapia Molecular Dirigida , PronósticoRESUMEN
Serum and glucocorticoid-regulated kinase 1 (SGK1) is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL). However, little is known about its function or the consequence of its mutation. The frequent finding of truncating mutations has led to the widespread assumption that these represent loss-of-function variants and, accordingly, that SGK1 must act as a tumor suppressor. In this study, instead, the most common SGK1 mutations led to production of aberrantly spliced messenger RNA neoisoforms in which translation is initiated from downstream methionines. The resulting N-terminal truncated protein isoforms showed increased expression related to the exclusion of an N-terminal degradation domain. However, they retained a functional kinase domain, the overexpression of which rendered cells resistant to AKT inhibition, in part because of increased phosphorylation of GSK3B. These findings challenge the prevailing assumption that SGK1 is a tumor-suppressor gene in DLBCL and provide the impetus to explore further the pharmacological inhibition of SGK1 as a therapeutic strategy for DLBCL.
Asunto(s)
Proteínas Inmediatas-Precoces/genética , Linfoma de Células B Grandes Difuso/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Cultivadas , Estabilidad de Enzimas , Humanos , Proteínas Inmediatas-Precoces/química , Proteínas Inmediatas-Precoces/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Fosforilación , Dominios Proteicos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.
Asunto(s)
Transformación Celular Viral , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/patogenicidad , Linfoma de Células B/patología , Células Plasmáticas/patología , Animales , Diferenciación Celular , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Infecciones por Virus de Epstein-Barr/virología , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Fibroblastos , Herpesvirus Humano 4/metabolismo , Humanos , Linfoma de Células B/virología , Ratones , Ratones Noqueados , Células Plasmáticas/virología , Cultivo Primario de Células , Transactivadores/genética , Transactivadores/metabolismo , Proteínas de la Matriz Viral/metabolismo , Proteínas Virales/metabolismoRESUMEN
The term diffuse large B-cell lymphoma (DLBCL) includes a heterogeneous collection of biologically distinct tumours. This heterogeneity currently presents a barrier to the successful deployment of novel, biologically targeted therapies. Molecular profiling studies have recently proposed new molecular classification systems. These have the potential to resolve the biological heterogeneity of DLBCL into manageable subgroups of tumours that rely on shared oncogenic programmes. In many cases these biological programmes straddle the boundaries of our existing systems for classifying B-cell lymphomas. Here we review the findings from these major molecular profiling studies with a specific focus on those that propose new genetic subgroups of DLBCL. We highlight the areas of consensus and discordance between these studies and discuss the implications for current clinical practice and for clinical trials. Finally, we address the outstanding challenges and solutions to the introduction of genomic subtyping and precision medicine in DLBCL.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Genómica/métodos , Linfoma de Células B Grandes Difuso/genética , Humanos , PronósticoRESUMEN
ZFP36L1 and ZFP36L2 are RNA-binding proteins (RBPs) that interact with AU-rich elements in the 3' untranslated region of mRNA, which leads to mRNA degradation and translational repression. Here we show that mice that lacked ZFP36L1 and ZFP36L2 during thymopoiesis developed a T cell acute lymphoblastic leukemia (T-ALL) dependent on the oncogenic transcription factor Notch1. Before the onset of T-ALL, thymic development was perturbed, with accumulation of cells that had passed through the beta-selection checkpoint without first expressing the T cell antigen receptor beta-chain (TCRbeta). Notch1 expression was higher in untransformed thymocytes in the absence of ZFP36L1 and ZFP36L2. Both RBPs interacted with evolutionarily conserved AU-rich elements in the 3' untranslated region of Notch1 and suppressed its expression. Our data establish a role for ZFP36L1 and ZFP36L2 during thymocyte development and in the prevention of malignant transformation.
Asunto(s)
Proteínas Nucleares/deficiencia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Linfocitos T/inmunología , Timo/inmunología , Tristetraprolina/deficiencia , Secuencia de Aminoácidos , Animales , Factor 1 de Respuesta al Butirato , Secuencia Conservada , Humanos , Inmunofenotipificación , Estimación de Kaplan-Meier , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/inmunología , Receptor Notch1/genética , Receptor Notch1/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Alineación de Secuencia , Timo/crecimiento & desarrollo , Transcripción Genética , Tristetraprolina/genética , Tristetraprolina/inmunologíaRESUMEN
Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of â¼4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.
Asunto(s)
Análisis Mutacional de ADN/métodos , Secuenciación del Exoma , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Investigación Biomédica/organización & administración , Niño , Preescolar , Estudios de Cohortes , Redes Comunitarias , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias Hematológicas/clasificación , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Humanos , Lactante , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/patología , Masculino , Oncología Médica/organización & administración , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular/métodos , Estadificación de Neoplasias , Pronóstico , Transcriptoma , Reino Unido , Secuenciación del Exoma/métodos , Adulto JovenRESUMEN
BACKGROUND: Urban malaria has received insufficient attention in the literature. The prevalence and clinical characteristics of Plasmodium falciparum infection amongst patients presenting with suspected malaria were investigated at a major urban hospital in Douala, Cameroon with a particular focus on anaemia. METHODS: A cross-sectional, 18-week demographic and clinical survey was conducted of patients presenting to the Emergency Department of Douala Military Hospital with suspected malaria, largely defined by the presence or recent history of fever. Venous samples were tested for P. falciparum using rapid diagnostic tests and PCR, and anaemia was defined by haemoglobin level according to WHO definitions. Likelihood ratios (LR), odds ratios (OR), and population attributable risk percent (PARP) were calculated. RESULTS: Participants were ages 8 months to 86 years, 51% were women (257/503), and all districts of Douala were represented. Overall, 38.0% (n = 189/497) were anaemic, including 5.2% (n = 26/497) with severe anaemia. Anaemia prevalence was significantly higher (OR: 2.20, 95% CI 1.41-3.45) among children < 15 years (53.1%, n = 52/98) compared to adults (34%, n = 133/392). Plasmodium falciparum was detected in 37.2% by nested PCR. Among all participants, several factors were associated with clinically significant LR for P. falciparum infection, including age 10-14 years (positive LR: 3.73), living in the island district of Douala VI (positive LR: 3.41), travel to any of three northern regions (positive LR: 5.11), and high fever > 40 °C at presentation (positive LR: 4.83). Among all participants, 8.7% of anaemia was associated with P. falciparum infection, while the PARP was 33.2% among those < 15 years of age and 81.0% among 10-14-year-olds. CONCLUSIONS: The prevalence of P. falciparum infection in the urban hospital was high. Mirroring trends in many rural African settings, older children had the highest positivity rate for P. falciparum infection. Anaemia was also common in all age groups, and for those 10-14 years of age, 80% of the risk for anaemia was associated with P. falciparum infection. Malaria rates in major urban population centres can be high, and more research into the multifactorial causes of anaemia across the age spectrum are needed.
Asunto(s)
Anemia , Malaria Falciparum , Malaria , Niño , Adulto , Estados Unidos , Humanos , Femenino , Adolescente , Anciano de 80 o más Años , Masculino , Plasmodium falciparum , Estudios Transversales , Hospitales Militares , Camerún/epidemiología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Malaria Falciparum/diagnóstico , Anemia/etiología , Malaria/complicaciones , Prevalencia , Hemoglobinas/análisis , Hospitales UrbanosRESUMEN
BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS: We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. RESULTS: We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS: We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).
Asunto(s)
Perfilación de la Expresión Génica , Heterogeneidad Genética , Linfoma de Células B Grandes Difuso/genética , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Epigénesis Genética , Exoma , Genotipo , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Pronóstico , Análisis de Secuencia de ADN , TranscriptomaRESUMEN
RNA-binding proteins (RBPs) regulate fundamental processes, such as differentiation and self-renewal, by enabling the dynamic control of protein abundance or isoforms or through the regulation of noncoding RNA. RBPs are increasingly appreciated as being essential for normal hematopoiesis, and they are understood to play fundamental roles in hematological malignancies by acting as oncogenes or tumor suppressors. Alternative splicing has been shown to play roles in the development of specific hematopoietic lineages, and sequence-specific mutations in RBPs lead to dysregulated splicing in myeloid and lymphoid leukemias. RBPs that regulate translation contribute to the development and function of hematological lineages, act as nodes for the action of multiple signaling pathways, and contribute to hematological malignancies. These insights broaden our mechanistic understanding of the molecular regulation of hematopoiesis and offer opportunities to develop disease biomarkers and new therapeutic modalities.
Asunto(s)
Neoplasias Hematológicas , Hematopoyesis/genética , Mutación , Proteínas de Neoplasias , ARN Neoplásico , ARN no Traducido , Proteínas de Unión al ARN , Animales , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , ARN no Traducido/genética , ARN no Traducido/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Retroperitoneal fibrosis and chronic periaortitis describe overlapping groups of rare diseases characterized by inflammation and fibrosis involving the aorta. The presentation is often non-specific, and while obstructive nephropathy is a common complication, these entities are an uncommon cause of renal failure necessitating dialysis. A 57-year-old man presented multiple times with acute kidney injury, even requiring hemodialysis, with repeated abrupt resolution. Renal ultrasound repeatedly did not reveal acute hydronephrosis. Renal biopsy on his first admission showed acute tubular injury attributed to hypovolemia. Computed tomography finally revealed a retroperitoneal soft tissue mass encasing the infrarenal abdominal aorta and partially encasing the bilateral ureters. Bilateral nephrostomy tubes were placed, steroids were initiated, and the patient experienced rapid and remarkable improvement in renal function. Chronic periaortitis should be considered in older patients with acute kidney injury, even in the absence of ultrasonographic evidence of obstruction. Additional studies are needed to describe the test characteristics of renal sonography for periaortitis, the long-term sequelae of acute kidney injury secondary to periaortitis, and the optimal management to preserve long-term renal function.
Asunto(s)
Lesión Renal Aguda , Fibrosis Retroperitoneal , Humanos , Riñón/patología , Masculino , Persona de Mediana EdadRESUMEN
The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3 Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface, we reveal a requirement for this protein-protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell-restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity.
Asunto(s)
Linfocitos B/citología , Diferenciación Celular , Supervivencia Celular , Linfoma de Células B Grandes Difuso/patología , Proteínas de Transporte de Catión Orgánico/fisiología , Animales , Línea Celular Tumoral , Ratones , Ratones Noqueados , Proteínas de Transporte de Catión Orgánico/genética , Transportador 2 de Cátion OrgánicoRESUMEN
Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. Whereas STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88, and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials.