RESUMO
Class switch recombination (CSR) plays an important role in adaptive immune response by enabling mature B cells to replace the initial IgM by another antibody class (IgG, IgE or IgA). CSR is preceded by transcription of the IgH constant genes and is controlled by the super-enhancer 3' regulatory region (3'RR) in an activation-specific manner. The 3'RR is composed of four enhancers (hs3a, hs1-2, hs3b and hs4). In mature B cells, 3'RR activity correlates with transcription of its enhancers. CSR can also occur in primary developing B cells though at low frequency, but in contrast to mature B cells, the transcriptional elements that regulate the process in developing B cells are ill-known. In particular, the role of the 3'RR in the control of constant genes' transcription and CSR has not been addressed. Here, by using a mouse line devoid of the 3'RR and a culture system that highly enriches in pro-B cells, we show that the 3'RR activity is indeed required for switch transcription and CSR, though its effect varies in an isotype-specific manner and correlates with transcription of hs4 enhancer only.
Assuntos
Cadeias Pesadas de Imunoglobulinas , Super Intensificadores , Cadeias Pesadas de Imunoglobulinas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Switching de Imunoglobulina/genética , Linfócitos B , Isotipos de Imunoglobulinas/genética , Elementos Facilitadores GenéticosRESUMO
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.
Assuntos
Cadeias Pesadas de Imunoglobulinas , Linfoma de Células B , Animais , Linfócitos B/patologia , Modelos Animais de Doenças , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Células B/genética , Linfoma de Células B/patologia , Camundongos , Camundongos Transgênicos , Sequências Reguladoras de Ácido NucleicoRESUMO
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.
Assuntos
Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Genes myc/genética , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Células B/genética , Animais , Elementos Facilitadores Genéticos , Humanos , Linfoma de Células B/patologia , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Translocação GenéticaRESUMO
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.
Assuntos
Dromaiidae , Linfoma de Células B , Animais , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Células B/genética , Camundongos , Camundongos Transgênicos , Sequências Reguladoras de Ácido NucleicoAssuntos
Linfócitos B/fisiologia , Diferenciação Celular , Cadeias Pesadas de Imunoglobulinas/genética , Sequências Reguladoras de Ácido Nucleico/fisiologia , Animais , Subpopulações de Linfócitos B/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Loci Gênicos , Humanos , Sequências Reguladoras de Ácido Nucleico/genéticaAssuntos
Linfócitos B/imunologia , Citidina Desaminase/genética , Elementos Facilitadores Genéticos/genética , Cadeias Pesadas de Imunoglobulinas/genética , Receptores de Antígenos de Linfócitos B/genética , Animais , Diferenciação Celular , Biologia Computacional , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Ensaios de Triagem em Larga Escala , Switching de Imunoglobulina , Ativação Linfocitária , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos B/metabolismoAssuntos
Linfócitos B/fisiologia , Elementos Facilitadores Genéticos/genética , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias kappa de Imunoglobulina/genética , Células Precursoras de Linfócitos B/fisiologia , Sequências Reguladoras de Ácido Nucleico/genética , Recombinação V(D)J/genética , Animais , Diferenciação Celular , Inativação Gênica , Genes RAG-1/genética , Switching de Imunoglobulina , Camundongos , Camundongos Knockout , Ativação TranscricionalAssuntos
Região 3'-Flanqueadora/genética , Região 5'-Flanqueadora/genética , Linfócitos B/imunologia , Elementos Facilitadores Genéticos , Cadeias Pesadas de Imunoglobulinas/genética , Região de Controle de Locus Gênico/genética , Sequências Reguladoras de Ácido Nucleico/genética , Animais , Células Cultivadas , Feminino , Proteínas de Homeodomínio/fisiologia , Switching de Imunoglobulina/genética , Masculino , Camundongos , Camundongos Knockout , Deleção de Sequência , Hipermutação Somática de Imunoglobulina , Transcrição GênicaRESUMO
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.
Assuntos
Linfócitos B/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Sequências Reguladoras de Ácido Nucleico/fisiologia , Imunidade Adaptativa , Animais , Linfócitos B/citologia , Linhagem Celular , Genes de Cadeia Pesada de Imunoglobulina/genética , Imunidade Inata , Camundongos , Análise de Sequência de DNA , Transcrição Gênica , Recombinação V(D)JAssuntos
Região 3'-Flanqueadora/genética , Subpopulações de Linfócitos B/fisiologia , Elementos Facilitadores Genéticos/genética , Imunoglobulina A/metabolismo , Cadeias Pesadas de Imunoglobulinas/genética , Peritônio/imunologia , Pleura/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Regulação da Expressão Gênica , Imunoglobulina A/genética , Switching de Imunoglobulina , Camundongos , Camundongos da Linhagem 129 , Camundongos KnockoutRESUMO
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.
