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1.
Immunity ; 39(2): 229-44, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23973221

RESUMO

The immunoglobulin heavy-chain (Igh) locus undergoes large-scale contraction in pro-B cells, which facilitates VH-DJH recombination by juxtaposing distal VH genes next to the DJH-rearranged gene segment in the 3' proximal Igh domain. By using high-resolution mapping of long-range interactions, we demonstrate that local interaction domains established the three-dimensional structure of the extended Igh locus in lymphoid progenitors. In pro-B cells, these local domains engaged in long-range interactions across the Igh locus, which depend on the regulators Pax5, YY1, and CTCF. The large VH gene cluster underwent flexible long-range interactions with the more rigidly structured proximal domain, which probably ensures similar participation of all VH genes in VH-DJH recombination to generate a diverse antibody repertoire. These long-range interactions appear to be an intrinsic feature of the VH gene cluster, because they are still generated upon mutation of the Eµ enhancer, IGCR1 insulator, or 3' regulatory region in the proximal Igh domain.


Assuntos
Diversidade de Anticorpos/genética , Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética , Genes de Cadeia Pesada de Imunoglobulina , Região Variável de Imunoglobulina/genética , Células Precursoras de Linfócitos B/imunologia , Animais , Sequência de Bases , Sítios de Ligação , Fator de Ligação a CCCTC , Mapeamento Cromossômico , Rearranjo Gênico , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição PAX5/metabolismo , Ligação Proteica , Proteínas Repressoras/metabolismo , Análise de Sequência de DNA , Fator de Transcrição YY1/metabolismo
2.
Nucleic Acids Res ; 45(10): 5829-5837, 2017 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-28369649

RESUMO

Cis-regulatory elements feature clustered sites for transcription factors, defining core enhancers and have inter-species homology. The mouse IgH 3΄ regulatory region (3'RR), a major B-cell super-enhancer, consists of four of such core enhancers, scattered throughout more than 25 kb of packaging 'junk DNA', the sequence of which is not conserved but follows a unique palindromic architecture which is conserved in all mammalian species. The 3'RR promotes long-range interactions and potential IgH loops with upstream promoters, controlling class switch recombination (CSR) and somatic hypermutation (SHM). It was thus of interest to determine whether this functional architecture also involves the specific functional structure of the super-enhancer itself, potentially promoted by its symmetric DNA shell. Since many transgenic 3'RR models simply linked core enhancers without this shell, it was also important to compare such a 'core 3'RR' (c3'RR) with the intact full-length super-enhancer in an actual endogenous IgH context. Packaging DNA between 3'RR core enhancers proved in fact to be necessary for optimal SHM, CSR and IgH locus expression in plasma cells. This reveals that packaging DNA can matter in the functional anatomy of a super-enhancer, and that precise evaluation of such elements requires full consideration of their global architecture.


Assuntos
Regiões 3' não Traduzidas/imunologia , Elementos Facilitadores Genéticos/imunologia , Switching de Imunoglobulina/genética , Cadeias Pesadas de Imunoglobulinas/genética , Regiões Promotoras Genéticas/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , DNA/genética , DNA/imunologia , Loci Gênicos , Cadeias Pesadas de Imunoglobulinas/classificação , Cadeias Pesadas de Imunoglobulinas/imunologia , Camundongos , Camundongos Transgênicos , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/imunologia , Hipermutação Somática de Imunoglobulina/genética
3.
Proc Natl Acad Sci U S A ; 113(6): 1618-23, 2016 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-26831080

RESUMO

As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3' regulatory region (3'RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3'RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasi-palindromic structure. By comparing relevant previous knockout (KO) mouse models (3'RR KO and hs3b-4 KO) to a novel mutant devoid of the 3'RR quasi-palindromic region (3'PAL KO), we pinpointed common features and differences that specify two distinct regulatory entities acting sequentially during B-cell ontogeny. Independently of exogenous antigens, the 3'RR distal part, including hs4, fine-tuned B-cell receptor expression in newly formed and naïve B-cell subsets. At mature stages, the 3'RR portion including the quasi-palindrome dictated antigen-dependent locus remodeling (global somatic hypermutation and class switch recombination to major isotypes) in activated B cells and antibody production in plasma cells.


Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Animais , Formação de Anticorpos , Antígenos/metabolismo , Linfócitos B/metabolismo , Contagem de Células , Linhagem da Célula , Citometria de Fluxo , Marcação de Genes , Centro Germinativo/metabolismo , Heterozigoto , Switching de Imunoglobulina/genética , Imunoglobulina M/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Antissenso/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Deleção de Sequência , Hipermutação Somática de Imunoglobulina/genética , Transcrição Gênica
4.
J Immunol ; 193(3): 1171-83, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24965776

RESUMO

The IgH intronic enhancer region Eµ is a combination of both a 220-bp core enhancer element and two 310-350-bp flanking scaffold/matrix attachment regions named MARsEµ. In the mouse, deletion of the core-enhancer Eµ element mainly affects VDJ recombination with minor effects on class switch recombination. We carried out endogenous deletion of the full-length Eµ region (core plus MARsEµ) in the mouse genome to study VH gene repertoire and IgH expression in developing B-lineage cells. Despite a severe defect in VDJ recombination with partial blockade at the pro-B cell stage, Eµ deletion (core or full length) did not affect VH gene usage. Deletion of this regulatory region induced both a decrease of pre-B cell and newly formed B cell compartments and a strong orientation toward the marginal zone B cell subset. Because Igµ H chain expression was decreased in Eµ-deficient pre-B cells, we propose that modification of B cell homeostasis in deficient animals was caused by "weak" pre-B cell and BCR expression. Besides imbalances in B cell compartments, Ag-specific Ab responses were not impaired in animals carrying the Eµ deletion. In addition to its role in VDJ recombination, our study points out that the full-length Eµ region does not influence VH segment usage but ensures efficient Igµ-chain expression required for strong signaling through pre-B cells and newly formed BCRs and thus participates in B cell inflow and fate.


Assuntos
Subpopulações de Linfócitos B/imunologia , Elementos Facilitadores Genéticos/imunologia , Regulação da Expressão Gênica/imunologia , Genes de Cadeia Pesada de Imunoglobulina/imunologia , Região Variável de Imunoglobulina/genética , Cadeias mu de Imunoglobulina/genética , Animais , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/metabolismo , Movimento Celular/genética , Movimento Celular/imunologia , Deleção de Genes , Switching de Imunoglobulina/genética , Cadeias mu de Imunoglobulina/biossíntese , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Distribuição Aleatória , Receptores de Antígenos de Linfócitos B/biossíntese , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células-Tronco/citologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Recombinação V(D)J/genética , Recombinação V(D)J/imunologia
5.
Sci Rep ; 14(1): 7370, 2024 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-38548819

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 Genéticos
6.
J Biol Chem ; 287(11): 8356-60, 2012 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-22270371

RESUMO

V(D)J recombination occurs during the antigen-independent early steps of B-cell ontogeny. Multiple IgH cis-regulatory elements control B-cell ontogeny. IGCR1 (intergenic control region 1), the DQ52 promoter/enhancer, and the intronic Emu enhancer, all three located upstream of Cmu, have important roles during V(D)J recombination, whereas there is no clue about a role of the IgH regulatory region (RR) encompassing the four transcriptional enhancers hs3a, hs1,2, hs3b, and hs4 during these early stages. To clarify the role of the RR in V(D)J recombination, we totally deleted it in the mouse genome. Here, we show that V(D)J recombination is unaffected by the complete absence of the IgH RR, highlighting that this region only orchestrates IgH locus activity during the late stages of B-cell differentiation. In contrast, the earliest antigen-independent steps of B-cell ontogeny would be under the control of only the upstream Cmu elements of the locus.


Assuntos
Linfócitos B/metabolismo , Elementos Facilitadores Genéticos/fisiologia , Loci Gênicos/fisiologia , Cadeias Pesadas de Imunoglobulinas/metabolismo , Recombinação V(D)J/fisiologia , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/imunologia , Camundongos , Camundongos Mutantes
7.
Am J Pathol ; 180(4): 1688-701, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22326754

RESUMO

Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a monoclonal proliferation of lymphocytes with the co-expression of CD5 and CD43, but not of CD23. Typical MCL is associated with overexpression of cyclin D1, and blastoid MCL variants are associated with Myc (alias c-myc) translocations. In this study, we developed a murine model of MCL-like lymphoma by crossing Cdk4(R24C) mice with Myc-3'RR transgenic mice. The Cdk4(R24C) mouse is a knockin strain that expresses a Cdk4 protein that is resistant to inhibition by p16(INK4a) as well as other INK4 family members. Ablation of INK4 control on Cdk4 does not affect lymphomagenesis, B-cell maturation, and functions in Cdk4(R24C) mice. Additionally, B cells were normal in numbers, cell cycle activity, mitogen responsiveness, and Ig synthesis in response to activation. By contrast, breeding Cdk4(R24C) mice with Myc-3'RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma (CD19(+)IgM(+)IgD(+) cells) leads to the development of clonal blastoid MCL-like lymphoma (CD19(+)IgM(+)CD5(+)CD43(+)CD23(-) cells) in Myc/Cdk4(R24C) mice. Western blot analysis revealed high amounts of Cdk4/cyclin D1 complexes as the main hallmark of these lymphomas. These results indicate that although silent in nonmalignant B cells, a defect in the INK4-Cdk4 checkpoint can participate in lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation that might be reminiscent of the development of human blastoid MCL.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Genes myc , Linfoma de Célula do Manto/genética , Animais , Linfócitos B/imunologia , Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/imunologia , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Imunoglobulinas/biossíntese , Imunofenotipagem , Ativação Linfocitária/imunologia , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfopoese/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Hipermutação Somática de Imunoglobulina
8.
J Immunol ; 187(11): 5772-82, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22039300

RESUMO

Although c-myc is classically described as the driving oncogene in Burkitt's lymphoma (BL), deregulation and mutations of c-myc have been reported in multiple solid tumors and in other mature B cell malignancies such as mantle cell lymphoma (MCL), myeloma, and plasma cell lymphoma (PCL). After translocation into the IgH locus, c-myc is constitutively expressed under the control of active IgH enhancers. Those located in the IgH 3' regulatory region (3'RR) are master control elements of class switch recombination and of the transcriptional burst associated with plasma cell differentiation. c-myc-3'RR mice are prone to lymphomas with rather homogeneous, most often BL-like, phenotypes with incomplete penetrance (75% tumor incidence) and long latencies (10-12 mo). To reproduce c-myc-induced mature B cell lymphomagenesis in the context of an additional defect often observed in human lymphomas, we intercrossed c-myc-3'RR with p53(+/-) mice. Double transgenic c-myc-3'RR/p53(+/-) mice developed lymphoma with short latency (2-4 mo) and full penetrance (100% tumor incidence). The spectrum of B lymphomas occurring in c-myc-3'RR/p53(+/-) mice was widened, including nonactivated (CD43(-)) BL, activated (CD43(+)) BL, MCL-like lymphoma, and PCL, thus showing that 3'RR-mediated deregulation of c-myc can promote various types of B lymphoproliferation in cells that first acquired a p53 defect. c-myc/p53(+/-) mice closely reproduce many features of BL, MCL, and PCL and provide a novel and efficient model to dissect the molecular events leading to c-myc-induced lymphomagenesis and an important tool to test potential therapeutic agents on malignant B cells featuring various maturation stages.


Assuntos
Linfócitos B/patologia , Transformação Celular Neoplásica/genética , Genes myc/genética , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma/genética , Sequências Reguladoras de Ácido Nucleico/genética , Proteína Supressora de Tumor p53/genética , Animais , Separação Celular , Transformação Celular Neoplásica/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transgenes
9.
Blood ; 116(11): 1895-8, 2010 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-20538806

RESUMO

The immunoglobulin heavy chain locus (IgH) undergoes multiple changes along B-cell differentiation. In progenitor B cells, V(D)J assembly allows expression of µ heavy chains. In mature B cells, class switch recombination may replace the expressed constant (C)µ gene with a downstream C(H) gene. Finally, plasma cell differentiation strongly boosts IgH transcription. How the multiple IgH transcriptional enhancers tune these changes is unclear. Here we demonstrate that deletion of the whole IgH 3' regulatory region (3'RR) allows normal maturation until the stage of IgM/IgD expressing lymphocytes, but nearly abrogates class switch recombination to all C(H) genes. Although plasma cell numbers are unaffected, we reveal the role of the 3'RR into the transcriptional burst normally associated with plasma cell differentiation. Our study shows that transcriptional changes and recombinations occurring after antigen-encounter appear mainly controlled by the 3'RR working as a single functional unit.


Assuntos
Switching de Imunoglobulina/genética , Cadeias Pesadas de Imunoglobulinas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Deleção de Sequência , Animais , Apoptose , Linfócitos B/citologia , Linfócitos B/metabolismo , Linhagem Celular , Proliferação de Células , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunoglobulina D/genética , Imunoglobulina D/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Isotipos de Imunoglobulinas/genética , Isotipos de Imunoglobulinas/metabolismo , Imunoglobulina M/genética , Imunoglobulina M/metabolismo , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Recombinação Genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica
11.
Leuk Lymphoma ; 63(9): 2114-2125, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35481805

RESUMO

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 Nucleico
12.
Eur J Immunol ; 40(12): 3306-11, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21080376

RESUMO

The 3' regulatory region (3'RR) located downstream of the IgH gene is the master element that controls class switch recombination and sustains high-level transcription at the plasma-cell stage. This latter role suggests that the 3'RR may be involved in oncogene deregulation during the frequent IgH translocation events associated with B-cell malignancies. A convincing demonstration of the essential contribution of 3'RR in lymphomagenesis has been provided by transgenic animal models. The mouse 3'RR shares a strong structural homology with the regulatory regions located downstream of each human Cα gene. Mouse models exploring the role of the 3'RR in B-cell physiology and in malignancies should provide useful indications about the pathophysiology of human cell lymphocyte proliferation.


Assuntos
Regiões 3' não Traduzidas/genética , Linfócitos B/imunologia , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma/genética , Sequências Reguladoras de Ácido Nucleico/genética , Regiões 3' não Traduzidas/imunologia , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Modelos Animais de Doenças , Humanos , Linfoma/patologia , Camundongos , Camundongos Transgênicos , Sequências Reguladoras de Ácido Nucleico/imunologia
13.
J Immunol ; 182(11): 6926-32, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19454689

RESUMO

Several studies have reported that regulatory elements located 3' of the IgH locus (namely hs3a, hs1,2, hs3b, and hs4) might play a role during class switch recombination (CSR) and Ig synthesis. While individual deletion of hs3a or hs1,2 had no effect, pairwise deletion of hs3b (an inverted copy of hs3a) and hs4 markedly affected CSR and Ig expression. Among these two elements, hs4 was tentatively presented with the master role due to its unique status within the 3' regulatory region: distal position outside repeated regions, early activation in pre-B cells, strong activity throughout B cell ontogeny. To clarify its role, we generated mice with a clean deletion of the hs4 after replacement with a floxed neo(R) cassette. Surprisingly, and as for previous deletion of hs3a or hs1,2, deletion of hs4 did not affect either in vivo CSR or the secretion level of any Ig isotype. In vitro CSR and Ig secretion in response to LPS and cytokines was not affected either. The only noticeable effects of the hs4 deletion were a decrease in the number of B splenocytes and a decreased membrane IgM expression. In conclusion, while dispensable for CSR and Ig transcription in plasma cells, hs4 mostly appears to contribute to Ig transcription in resting B lymphocytes.


Assuntos
Elementos Facilitadores Genéticos/fisiologia , Switching de Imunoglobulina , Cadeias Pesadas de Imunoglobulinas/genética , Imunoglobulinas/biossíntese , Sequências Reguladoras de Ácido Nucleico , Animais , Linfócitos B , Imunoglobulina M/genética , Camundongos , Camundongos Knockout , Baço/citologia
14.
Biochim Biophys Acta ; 1793(2): 418-26, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19026697

RESUMO

Burkitt lymphoma (BL) features translocations linking c-myc to the immunoglobulin heavy chain (IgH) locus. By inserting a c-myc gene under the control of the 3'IgH locus control region (LCR) into the mouse genome, we generated c-myc-3'LCR mice that develop clonal BL or diffuse anaplastic lymphoma. We show in the present study that while BL from c-myc-3'LCR mice would be classified as pre-germinal center (GC) cells due to the absence of both BCL-6 expression and somatic hypermutation (SHM) in V(H) sequences, they show a high level of SHM focused on the c-myc oncogene itself. This observation suggests that the c-myc-3'IgH LCR tandem association drives development of lymphoma from naïve B cells by specifically recruiting AID activity on c-myc in a process that early becomes independent from antigen selection and where the successive rounds of SHM rather rely on the selection of the most efficient mutations for oncogene deregulation. Similar to the translocated c-myc gene in human BL, mutations were found in first exon and 5' flanking sequences of transgenic c-myc and specially focused on negative regulatory elements, thus leading to high and constitutive oncogene expression. In conclusion while 3'IgH transcriptional enhancers in c-myc-3'LCR mice first simply act in cis to slightly stimulate c-myc transcription in untransformed B cells, the occurrence of lymphoma appears to result from an additional mechanism necessitating AID-driven mutations within the first exon and 5' flanking sequences which does not occur in parallel but rather circumvents antigen-driven selection.


Assuntos
Genes myc/genética , Linfoma/genética , Mutação/genética , Hipermutação Somática de Imunoglobulina/genética , Região 5'-Flanqueadora/genética , Animais , Linfoma de Burkitt/genética , Linfoma de Burkitt/imunologia , Linfoma de Burkitt/patologia , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Éxons/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Região de Controle de Locus Gênico/genética , Linfoma/imunologia , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-bcl-6 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Front Immunol ; 11: 1564, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793219

RESUMO

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 Genética
16.
Blood Adv ; 4(1): 28-39, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31899800

RESUMO

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 Nucleico
17.
Mediators Inflamm ; 2009: 689430, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20339511

RESUMO

In view of the important oncogenic action of phospholipase A(2)(PLA(2)) we investigated PLA(2) transcripts in human meningiomas. Real-time PCR was used to investigate PLA(2) transcripts in 26 human meningioma tumors. Results indicated that three Ca(2+)-dependent high molecular weight PLA(2) (PLA(2)-IVA, PLA(2)-IVB, PLA(2)-IVC), one Ca(2+)-independent high molecular weight PLA(2) (PLA(2)-VI) and five low molecular weight secreted forms of PLA(2) (PLA(2)-IB, PLA(2)-IIA, PLA(2)-III, PLA(2)-V, and PLA(2)-XII) are expressed with PLA(2)-IVA, PLA(2)-IVB, PLA(2)-VI, and PLA(2)-XIIA as the major expressed forms. PLA(2)-IIE, PLA(2)-IIF, PLA(2)-IVD, and PLA(2)-XIIB are not detected. Plasma (PLA(2)-VIIA) and intracellular (PLA(2)-VIIB) platelet-activating factor acetylhydrolase transcripts are expressed in human meningiomas. However no difference was found for PLA(2) transcript amounts in relation to the tumor grade, the subtype of meningiomas, the presence of inflammatory infiltrated cells, of an associated edema, mitosis, brain invasion, vascularisation or necrosis. In conclusion numerous genes encoding multiples forms of PLA(2) are expressed in meningiomas where they might act on the phospholipid remodeling and on the local eicosanoid and/or cytokine networks.


Assuntos
Neoplasias Meníngeas/genética , Neoplasias Meníngeas/metabolismo , Meningioma/genética , Meningioma/metabolismo , Fosfolipases A2/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Fosfolipases A2/classificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Leuk Res ; 32(11): 1756-62, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18561999

RESUMO

Several reports have demonstrated an important role of leukotriene B(4) (LTB(4)) in the immune system. We investigated whether leukemic blasts from acute myeloid leukemic (AML) and acute lymphoid leukemic (ALL) patients produced LTB(4), 12- and 15-hydroxyeicosatetraenoic acids (12-HETE and 15-HETE) and whether these compounds affected blast proliferation and apoptosis. Leukemic blasts from AML M(0-2) and ALL patients expressed 5-LOX, 12-LOX and 15-LOX transcripts. Quantitative polymerase chain reaction indicated that 5-LOX transcripts were far more abundant than 12-LOX and 15-LOX ones. Leukemic blasts expressed 5-LOX activating protein (FLAP) transcripts and produced LTB(4) in response to calcium ionophore. In contrast no 15-HETE production was found. Calcium ionophore-stimulated leukemic blasts produced 12-HETE but also released thromboxane A(2) suggesting that contaminating platelets accounted for the release of these compounds. No significant effect of LTB(4), 12-HETE or 15-HETE could be documented on leukemic blast growth and on their apoptose rate. Results of the present study indicate that immature form of leukemic blasts produce LTB(4). However, the three major lipoxygenase metabolites of arachidonic acid; i.e., LTB(4), 12-HETE or 15-HETE, had no evident effect on their growth and apoptosis. We may speculate that LTB(4)-derived blast cells might initiate, augment or prolong tissue inflammation and damages by affecting the marrow and blood cytokine network.


Assuntos
Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , Crise Blástica/enzimologia , Leucemia Mieloide Aguda/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Apoptose/fisiologia , Araquidonato 12-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/genética , Ácido Araquidônico/metabolismo , Crise Blástica/classificação , Crise Blástica/patologia , Cálcio/metabolismo , Proliferação de Células , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Ionóforos/farmacologia , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/patologia , Leucotrieno B4/metabolismo , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tromboxano A2/metabolismo
19.
Blood Adv ; 2(3): 252-262, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29437640

RESUMO

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)J
20.
Leuk Res ; 31(3): 399-402, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16837045

RESUMO

Platelet-activating factor (PAF) is a phospholipid mediator with potent immunoregulatory activities on mature leukocytes. PAF modulates leukocyte cytosolic Ca2+ concentration ([Ca2+]i) through a Gq mediated pathway. We highlight, for the first time, Gq transcripts, PAF receptor (PAF-R) transcripts and protein in blast cells of acute myeloid (AML) and lymphoid (ALL) leukemia patients. PAF stimulated [Ca2+]i in leukemic blast cells; PAF effects being prevented by a specific PAF-R antagonist. In conclusion, functional PAF-R are present in blast cells of patients with acute leukemia; a result that could be of physiologic importance regarding the important effect of PAF on leukocytes maturation and functions.


Assuntos
Crise Blástica , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patologia , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Doença Aguda , Cálcio/metabolismo , Humanos , Leucemia Linfoide/genética , Leucemia Mieloide/genética , Glicoproteínas da Membrana de Plaquetas/genética , Receptores Acoplados a Proteínas G/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transcrição Gênica
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