RESUMEN
Treatment with immune checkpoint inhibitors (ICIs) is frequently associated with immune-related adverse events (irAEs). A new study identified an interleukin 7 (IL-7) allelic variant-rs16906115-as a major risk factor for the development of ICI-associated irAEs. This association is of great significance as it indicates that germline genetic variants influence the occurrence of irAEs, thus opening a new avenue for identifying high-risk patients to enable better management of ICI therapy and associated irAEs.
Asunto(s)
Antineoplásicos Inmunológicos , Interleucina-7 , Humanos , Células Germinativas , Inmunoterapia , Interleucina-7/genética , Estudios Retrospectivos , Factores de RiesgoRESUMEN
IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.
Asunto(s)
Endorribonucleasas , Neoplasias , Animales , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Inmunidad , Ratones , Procesos Neoplásicos , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
The 3' regulatory region (3'RR) located downstream from the Cα gene is the conductor of transcription, accessibility, and remodeling of the IgH locus at mature B-cell stages. Convincing demonstrations of the essential contributions of the 3'RR in B-cell lymphomagenesis have been provided by mouse models which bring the oncogene c-Myc under the 3'RR transcriptional control. In this study, we developed a mouse model of CD138+ plasma B-cell lymphomas. If the KI of c-myc directly into Cα just 5' to the 3'RR in iMycCα mice produced B-cell lymphomas with low kinetics, we enforced c-myc production in iMycCα mice by the generation of homozygous c-myc transgenic mice. Our results show that homozygous iMycCα mice lead to a mouse model of plasma CD138+ B-cell lymphomas with interesting and wide transcriptomic similarities to human multiple myeloma and appropriated emergence kinetics that can be used to test new experimental therapeutic approaches.
Asunto(s)
Cadenas Pesadas de Inmunoglobulina , Linfoma de Células B , Animales , Linfocitos B/patología , Modelos Animales de Enfermedad , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma de Células B/genética , Linfoma de Células B/patología , Ratones , Ratones Transgénicos , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
Chromosomal translocations linking various oncogenes to transcriptional enhancers of the immunoglobulin heavy chain (IgH) locus are often implicated as the cause of B-cell malignancies. Two major IgH transcriptional enhancers have been reported so far. The Eµ enhancer located upstream of the Cµ gene controls early events in B-cell maturation such as VDJ recombination. The 3' regulatory region (3'RR) located downstream from the Cα gene controls late events in B-cell maturation such as IgH transcription, somatic hypermutation, and class switch recombination. Convincing demonstrations of the essential contributions of both Eµ and 3'RR in B-cell lymphomagenesis have been provided by transgenic and knock-in animal models which bring the oncogene c-myc under Eµ/3'RR transcriptional control. This short review summarizes the different mouse models so far available and their interests/limitations for progress in our understanding of human c-myc-induced B-cell lymphomagenesis.
Asunto(s)
Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Genes myc/genética , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma de Células B/genética , Animales , Elementos de Facilitación Genéticos , Humanos , Linfoma de Células B/patología , Ratones , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Translocación GenéticaRESUMEN
Numerous B-cell lymphomas feature translocations linking oncogenes to different locations in the immunoglobulin heavy chain (IgH) locus. During Burkitt lymphoma (BL), IgH breakpoints for c-myc translocation stand either close to JH segments or within switch regions. Transcription, accessibility, and remodeling of the IgH locus are under the control of the 2 potent cis-acting enhancer elements: Eµ and the 3' regulatory region (3'RR). To ensure their respective contributions to oncogene deregulation in the context of the endogenous IgH locus, we studied transgenic mice harboring a knock-in of c-myc in various positions of the IgH locus (3' to JH segments, 5' to Cµ with Eµ deletion and Cα). The observed spectrum of tumors, kinetics of emergence, and transcriptome analysis provide strong evidence that both Eµ and 3'RR deregulate c-myc and cooperate together to promote B-cell lymphomagenesis. Transgenics mimicking endemic BL (with c-myc placed 3' to JH segments) exhibited the highest rate of B-cell lymphoma emergence, the highest Ki67 index of proliferation, and the highest transcriptomic similarities to human BL. The 3'RR enhancer alone deregulated c-myc and initiated the development of BL-like lymphomas, suggesting that its targeting would be of therapeutic interest to reduce c-myc oncogenicity in vivo.
Asunto(s)
Dromaiidae , Linfoma de Células B , Animales , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma de Células B/genética , Ratones , Ratones Transgénicos , Secuencias Reguladoras de Ácidos NucleicosAsunto(s)
Linfocitos B/fisiología , Diferenciación Celular , Cadenas Pesadas de Inmunoglobulina/genética , Secuencias Reguladoras de Ácidos Nucleicos/fisiología , Animales , Subgrupos de Linfocitos B/fisiología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Sitios Genéticos , Humanos , Secuencias Reguladoras de Ácidos Nucleicos/genéticaAsunto(s)
Linfocitos B/inmunología , Citidina Desaminasa/genética , Elementos de Facilitación Genéticos/genética , Cadenas Pesadas de Inmunoglobulina/genética , Receptores de Antígenos de Linfocitos B/genética , Animales , Diferenciación Celular , Biología Computacional , Reparación del ADN por Unión de Extremidades , Reparación del ADN , Ensayos Analíticos de Alto Rendimiento , Cambio de Clase de Inmunoglobulina , Activación de Linfocitos , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos B/metabolismoAsunto(s)
Linfocitos B/fisiología , Elementos de Facilitación Genéticos/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/genética , Células Precursoras de Linfocitos B/fisiología , Secuencias Reguladoras de Ácidos Nucleicos/genética , Recombinación V(D)J/genética , Animales , Diferenciación Celular , Silenciador del Gen , Genes RAG-1/genética , Cambio de Clase de Inmunoglobulina , Ratones , Ratones Noqueados , Activación TranscripcionalAsunto(s)
Región de Flanqueo 3'/genética , Región de Flanqueo 5'/genética , Linfocitos B/inmunología , Elementos de Facilitación Genéticos , Cadenas Pesadas de Inmunoglobulina/genética , Región de Control de Posición/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Animales , Células Cultivadas , Femenino , Proteínas de Homeodominio/fisiología , Cambio de Clase de Inmunoglobulina/genética , Masculino , Ratones , Ratones Noqueados , Eliminación de Secuencia , Hipermutación Somática de Inmunoglobulina , Transcripción GenéticaRESUMEN
The immunoglobulin heavy chain (IgH) 3' regulatory region (3'RR) superenhancer controls B2 B-cell IgH transcription and cell fate at the mature stage but not early repertoire diversity. B1 B cells represent a small percentage of total B cells differing from B2 B cells by several points such as precursors, development, functions, and regulation. B1 B cells act at the steady state to maintain homeostasis in the organism and during the earliest phases of an immune response, setting them at the interface between innate and acquired immunity. We investigated the role of the 3'RR superenhancer on B1 B-cell fate. Similar to B2 B cells, the 3'RR controls µ transcription and cell fate in B1 B cells. In contrast to B2 B cells, 3'RR deletion affects B1 B-cell late repertoire diversity. Thus, differences exist for B1 and B2 B-cell 3'RR control during B-cell maturation. For the first time, these results highlight the contribution of the 3'RR superenhancer at this interface between innate and acquired immunity.
Asunto(s)
Linfocitos B/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Secuencias Reguladoras de Ácidos Nucleicos/fisiología , Inmunidad Adaptativa , Animales , Linfocitos B/citología , Línea Celular , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Inmunidad Innata , Ratones , Análisis de Secuencia de ADN , Transcripción Genética , Recombinación V(D)JAsunto(s)
Región de Flanqueo 3'/genética , Subgrupos de Linfocitos B/fisiología , Elementos de Facilitación Genéticos/genética , Inmunoglobulina A/metabolismo , Cadenas Pesadas de Inmunoglobulina/genética , Peritoneo/inmunología , Pleura/inmunología , Animales , Diferenciación Celular , Linaje de la Célula , Regulación de la Expresión Génica , Inmunoglobulina A/genética , Cambio de Clase de Inmunoglobulina , Ratones , Ratones de la Cepa 129 , Ratones NoqueadosRESUMEN
The four transcriptional enhancers located in the 3' regulatory region (3'RR) of the IgH locus control the late phases of B-cell maturation, namely IgH locus transcription, somatic hypermutation and class switch recombination. Doctor Jekyll by nature, the 3'RR acts as Mister Hyde in case of oncogenic translocation at the IgH locus taking under its transcriptional control the translocated oncogene. The aim of this review is to show this duality on the basis of the latest scientific advances in the structure and function of the 3'RR and to hIghlight the targeting of the 3'RR as a potential therapeutic approach in mature B-cell lymphomas.