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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(7): 690-695, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31315770

RESUMO

OBJECTIVE: To study the clinical features of acute lymphoblastic leukemia (ALL) in children with IKAROS family zinc finger 1 (IKZF1) deletion, and to observe the effect of increasing the intensity of chemotherapy on the prognosis of this disease. METHODS: A total of 278 children diagnosed with ALL between December 2015 and February 2018 were systematically treated according to the Chinese Children's Leukemia Group-ALL 2008 protocol (CCLG-ALL 2008). The patients were divided into an IKZF1-deleted group and a control group according to the presence or absence of IKZF1. The IKZF1-deleted group was treated with the regimen for high-risk group (HR) in the CCLG-ALL 2008 protocol, while the control group received different intensities of chemotherapy according to clinical risk classification. The clinical features and event-free survival rate (EFS) were compared between the two groups. RESULTS: A total of 24 (8.6%) cases of 278 children were found to have large deletions of exons of the IKZF1 gene. The IKZF1-deleted group had significantly higher proportions of cases with white blood cell count ≥50×109/L at initial diagnosis, BCR-ABL1 fusion gene positive, minimal residual disease ≥10% on the 15th day of induction remission treatment, minimal residual disease-high risk and clinical risk classification-high risk compared with the control group (P<0.05). The 3-year EFS rate (76%±10%) in the IKZF1-deleted group was lower than that in the control group (84%±4%), but with no significant difference between the two groups (P=0.282). The estimated 3-year EFS rate in the IKZF1-deleted-non-HR group (actually treated with the chemotherapy regimen for HR in the CCLG-ALL 2008 protocol) was 82%±12%, which was lower than that in the control-non-HR group (86%±5%), but there was no significant difference (P=0.436). CONCLUSIONS: ALL children with IKZF1 deletion have worse early treatment response, and increasing the intensity of chemotherapy might improve the prognosis.


Assuntos
Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Intervalo Livre de Doença , Deleção de Genes , Humanos , Neoplasia Residual , Prognóstico
2.
Rinsho Ketsueki ; 60(6): 708-715, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281164

RESUMO

Lymphoproliferative disorders (LPDs) are caused by dysregulated lymphocyte proliferation and include polyclonal benign and monoclonal malignant diseases. LPDs frequently occur in immunocompromized patients, particularly those with primary immunodeficiency disease (PID), a monogenic disease. PID-associated LPD corresponds to inherited LPD. Here, we describe inherited LPD and focus on IKZF1-associated diseases and Epstein-Barr virus-associated LPD, such as ZAP70 deficiency and X-linked lymphoproliferative syndrome type 1 with somatic reversion mosaicism. Disclosing the pathogenesis of inherited LPDs would lead to a broad understanding of LPDs and development of new treatment strategies.


Assuntos
Síndromes de Imunodeficiência/complicações , Transtornos Linfoproliferativos/genética , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Humanos , Fator de Transcrição Ikaros/genética
3.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096545

RESUMO

Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified: CREBBP-SRGAP2B, DNAH14-IKZF1, ETV6-SNUPN, ETV6-NUFIP1. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as IKZF1, CREBBP, and ETV6. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets.


Assuntos
Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Adolescente , Adulto , Proteína de Ligação a CREB/genética , Criança , Pré-Escolar , Dineínas/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Humanos , Fator de Transcrição Ikaros/genética , Lactente , Masculino , México , Proteínas Nucleares/genética , Prognóstico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas de Ligação ao Cap de RNA/genética , Proteínas de Ligação a RNA/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Adulto Jovem
4.
Nat Commun ; 10(1): 1911, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015454

RESUMO

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Cadeias lambda de Imunoglobulina/genética , Mieloma Múltiplo/diagnóstico , Proteínas do Mieloma/genética , Translocação Genética , Antineoplásicos/uso terapêutico , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/imunologia , Elementos Facilitadores Genéticos , Loci Gênicos , Genoma Humano , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Plasmócitos/imunologia , Plasmócitos/patologia , Prognóstico , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Recidiva , Análise de Sobrevida , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Sequenciamento Completo do Genoma
5.
Cytogenet Genome Res ; 158(1): 10-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974435

RESUMO

The IKZF1 gene is formed by 8 exons and encodes IKAROS, a transcription factor that regulates the expression of genes that control cell cycle progression and cell survival. In general, 15-20% of the patients with preB acute lymphoblastic leukemia (preB ALL) harbor IKZF1 deletions, and the frequency of these deletions increases in BCR-ABL1 or Ph-like subgroups. These deletions have been associated with poor treatment response and the risk of relapse. The aim of this descriptive study was to determine the frequency of IKZF1 deletions and the success of an induction therapy response in Mexican pediatric patients diagnosed with preB ALL in 2 hospitals from 2017 to August 2018. Thirty-six bone marrow samples from patients at the Instituto Nacional de Pediatría in Mexico City and the Centro Estatal de Cancerología in Tepic were analyzed. The IKZF1 deletion was identified by MLPA using the SALSA MLPA P335 ALL-IKZF1 probemix. Deletions of at least 1 IKZF1 exon were observed in 7/34 samples (20.6%): 3 with 1 exon deleted; 1 with 2 exons, 1 with 5 exons, 1 with 6 exons, and 1 patient with a complete IKZF1 deletion. This study was descriptive in nature; we calculated the frequency of the IKZF1 gene deletion in a Mexican pediatric population with preB ALL as 20.6%.


Assuntos
Fator de Transcrição Ikaros/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/química , Medula Óssea/patologia , Criança , Pré-Escolar , Éxons/genética , Feminino , Frequência do Gene , Genes Neoplásicos , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , México , Tipagem de Sequências Multilocus , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Indução de Remissão , Deleção de Sequência , Resultado do Tratamento
6.
Genet Test Mol Biomarkers ; 23(3): 176-179, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30810385

RESUMO

BACKGROUND: Leukemia is a heterogeneous disorder, characterized by elevated proliferation of white blood cells. Various genetic studies have assessed the contributory roles of several single nucleotide polymorphisms with the development of leukemia. The role of genetic variation in the ARID5B and IKZF1 genes has previously been identified in various population groups; however, the role of these variants in the north Indian populations of Jammu and Kashmir is unknown. AIM: In this study, we explored the association of the newly identified genetic variants, rs10740055 of ARID5B and rs6964823 of IKZF1, with leukemic patients from Jammu and Kashmir of northern India. METHODS: The variants were genotyped using TaqMan allele discrimination assays for 616 individuals (210 leukemic cases and 406 healthy controls). The association of each SNP with the disease was evaluated using logistic regression. RESULTS: It was observed that the variants rs6964823 (IKZF1) and rs10740055 (ARID5B) showed significant associations with odds ratio (OR) and p-values of 1.5 (1.0-2.3 at 95% confidence interval [CI]) and 0.04; and 2.5 (1.5-4.1 at 95% CI) and 0.0002, respectively. We also evaluated the cumulative effect for both the variants by combining the risk genotypes and obtained and OR of 4.9. DISCUSSION: It was found that the variants rs10740055 of ARID5B and rs6964823 of IKZF1 act individually and additively as risk factors in the development of leukemia in the populations of Jammu and Kashmir in Northern India.


Assuntos
Proteínas de Ligação a DNA/genética , Fator de Transcrição Ikaros/genética , Leucemia/genética , Fatores de Transcrição/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Proteínas de Ligação a DNA/fisiologia , Epistasia Genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fator de Transcrição Ikaros/fisiologia , Índia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Risco , Fatores de Transcrição/fisiologia
7.
J Immunol ; 202(4): 1112-1123, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30635395

RESUMO

CD4 Th cells are organizers of the immune response, directing other immune cells to initiate and maintain effective humoral and cellular immunity. CD4 T cells differentiate into distinct Th effector or regulatory subsets in response to signals delivered to them during the course of infection. Ikaros is a transcription factor that is expressed in blood cells from the level of the hematopoietic stem cell. It is required for normal thymic T cell development and serves as a tumor suppressor, as lack of Ikaros in developing lymphoid cells results in leukemia. To study the role of Ikaros in CD4 T cell differentiation and function, an Ikaros conditional knockout mouse was developed such that Ikaros expression was deleted specifically in mature T cells, thus avoiding defects observed in germline Ikaros mutant mice. Using this model system, we have shown that in the absence of Ikaros, CD4 T cells are able to attain Th1, Th2, and Th17, but not inducible regulatory T, cell fates. However, they show enhanced expression of a cohort of proinflammatory cytokines, resulting in differentiation of Th17 cells with a phenotype that has been associated with autoimmunity and pathological inflammation. In addition, we define Ikaros as a repressor of the gene program associated with the response to type I IFNs, another key pathway whose deregulation is linked to autoimmunity. Taken together, these data definitively define Ikaros as a critical regulator at the center of the inflammatory response in T cells and highlight a potential role in suppressing autoimmunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fator de Transcrição Ikaros/imunologia , Inflamação/imunologia , Animais , Feminino , Fator de Transcrição Ikaros/deficiência , Fator de Transcrição Ikaros/genética , Inflamação/genética , Interferon Tipo I/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação
9.
Genes Chromosomes Cancer ; 58(6): 396-401, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30578688

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy with few molecular alterations showing a consensual prognostic value. CRLF2 overexpression was recently identified in high-risk T-ALL patients. For these cases, no genomic abnormality was found to be associated with CRLF2 overexpression. IKZF1 has been recently shown to be a direct transcriptional regulator of CRLF2 expression. Moreover, it is known that NOTCH1 antagonizes IKZF1 in T-ALL. In light of these pieces of evidence, we reasoned that IKZF1 binding perturbation and CRLF2 upregulation could be associated in T-ALL. We evaluated two independent series of pediatric T-ALL cases (PHOP, n = 57 and TARGET, n = 264) for the presence of common T-ALL molecular abnormalities, such as NOTCH1/FBXW7 mutations. We also assessed CRLF2 and IKZF1 gene expression. CRLF2 overexpression was observed in 14% (PHOP) and 16% (TARGET) of T-ALL patients. No correlation was found between mRNA expression of CRLF2 and IKZF1 in both cohorts. Interestingly, we show that patients with mutations affecting NOTCH1-PEST domain and/or FBXW7 had higher CRLF2 expression (P = .04). In summary, we demonstrate for the first time that only mutations resulting in ICN1 (intracellular domain of NOTCH1) stabilization are associated with CRLF2 overexpression.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptor Notch1/genética , Receptores de Citocinas/genética , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Mutação , Ligação Proteica , Domínios Proteicos , Estabilidade Proteica , Receptor Notch1/química , Receptor Notch1/metabolismo , Receptores de Citocinas/metabolismo
10.
J Exp Med ; 216(1): 231-243, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30545902

RESUMO

Expression of Rag1 and Rag2 is tightly regulated in developing T cells to mediate TCR gene assembly. Here we have investigated the molecular mechanisms governing the assembly and disassembly of a transcriptionally active RAG locus chromatin hub in CD4+CD8+ thymocytes. Rag1 and Rag2 gene expression in CD4+CD8+ thymocytes depends on Rag1 and Rag2 promoter activation by a distant antisilencer element (ASE). We identify GATA3 and E2A as critical regulators of the ASE, and Runx1 and E2A as critical regulators of the Rag1 promoter. We reveal hierarchical assembly of a transcriptionally active chromatin hub containing the ASE and RAG promoters, with Rag2 recruitment and expression dependent on assembly of a functional ASE-Rag1 framework. Finally, we show that signal-dependent down-regulation of RAG gene expression in CD4+CD8+ thymocytes depends on Ikaros and occurs with disassembly of the RAG locus chromatin hub. Our results provide important new insights into the molecular mechanisms that orchestrate RAG gene expression in developing T cells.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Regulação da Expressão Gênica/fisiologia , Loci Gênicos/fisiologia , Proteínas de Homeodomínio/biossíntese , Timócitos/metabolismo , Transcrição Genética/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Antígenos CD4/genética , Antígenos CD4/metabolismo , Antígenos CD8/genética , Antígenos CD8/metabolismo , Proteínas de Ligação a DNA/genética , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Proteínas de Homeodomínio/genética , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Camundongos , Elementos de Resposta/fisiologia , Timócitos/citologia
11.
Curr Med Sci ; 38(1): 58-63, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30074152

RESUMO

Regulatory T cells (Tregs) play a pivotal role in the pathological development of hypertension. Helios, a transcription factor from the Ikaros family, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with suppression function, however, little has been known about its role in hypertension. This study was aimed to find whether Helios+ Tregs really play a vital role in hypertension. A total of 60 hypertension patients, and 46 normotension subjects were enrolled in this study. Frequencies of different Tregs subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was determined by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was detected by RT-PCR. Proportion of CD4+Foxp3+Helios+ Tregs was decreased significantly in patients with hypertension (62.52%±1.18% vs. 71.89%±1.03%, P<0.01), and it was correlated with plasma level of IL-10 positively (a=0.505, P<0.05) and plasma level of IFN-gamma negatively (r=-0.551, P<0.05). The mRNA expression of Foxp3 (7.23±1.00 vs. 10.58±0.54, P<0.05) and Helios (8.47±0.95 vs. 15.52±2.0, P<0.05) was decreased in CD4+ T cells from patients with hypertension. Helios+ Tregs were decreased in patients with hypertension and may play a protective role in hypertension progression.


Assuntos
Hipertensão/metabolismo , Fator de Transcrição Ikaros/genética , Linfócitos T Reguladores/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Hipertensão/sangue , Fator de Transcrição Ikaros/metabolismo , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Immunol Invest ; 47(6): 632-642, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29851536

RESUMO

BACKGROUND: The control of auto-reactive cells is defective in rheumatoid arthritis (RA). Regulatory T (Treg) cells which play a key role in the modulation of immune responses have an impaired function in RA. Foxp3 is a master regulator of Treg cells which its expression is under the tight control of epigenetic mechanisms. In the current study, we analyzed the epigenetic modulation of the Foxp3 Treg-specific demethylated region (TSDR) and Helios gene expression to determine Treg cells alteration in RA patients. METHODS: We have recruited 20 newly diagnosed patients with RA and 41 healthy controls in our study. The measurement of Foxp3 and Helios gene expression was performed by the real-time PCR technique and the methylation level of TSDR was analyzed by bisulfite treatment and quantitative methylation-specific PCR (Q-MSP). RESULTS: We found that RA patients had significantly lower level of Foxp3 gene expression and TSDR demethylation compared to healthy subjects (P < 0.001 and P = 0.006, respectively). Inversely, the Helios gene expression was elevated significantly in RA patients group (P = 0.048). We also observed a significant correlation between Foxp3 and Helios gene expression (P = 0.016) as well as a significant correlation between FoxP3 expression and demethylation rate of TSDR (P = 0.010). CONCLUSION: Our results suggested that both epigenetic modifications and Helios gene expression may have important roles in the pathogenesis of RA through their effects on Foxp3 gene expression.


Assuntos
Artrite Reumatoide/genética , Metilação de DNA/genética , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/genética , Fator de Transcrição Ikaros/genética , Linfócitos T Reguladores/imunologia , Actinas/genética , Actinas/metabolismo , Adulto , Estudos de Casos e Controles , Epigênese Genética/genética , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Fator de Transcrição Ikaros/biossíntese , Masculino
13.
Med Sci Monit ; 24: 2809-2817, 2018 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-29729093

RESUMO

BACKGROUND Baicalein can suppress the growth of multiple tumors, including multiple myeloma (MM), but the exact mechanisms remains elusive. Here, we investigated the exact mechanisms of the anti-myeloma activity of baicalein. MATERIAL AND METHODS Proliferation and rates of apoptosis of myeloma U266 cells exposed to baicalein were detected. Microarray, polymerase chain reaction (PCR) assay, and Western blot analysis were applied to evaluate the mRNA and protein levels of associated molecules. Survival analysis of IKZF1 and IKZF3 was conducted as well. RESULTS Baicalein suppressed the growth and stimulated apoptosis of myeloma U266 cells in a dose- and time-dependent way. Baicalein increased mRNA level of CRBN, and further studies suggested that baicalein downregulated IKZF1 and IKZF3 on a post-transcriptional level. Although the differences did not reach statistical significance, IKZF1 and IKZF3 were associated with poor overall survival. CONCLUSIONS Our results suggest that baicalein suppresses the growth and promotes apoptosis of myeloma U266 cells through downregulating IKZF1 and IKZF3. Baicalein increased the expression of CRBN, which might exert a reversion effect on resistance of IMiDs. MM patients in IKZF1 and IKZF3 low-expression groups had better overall survival than those in IKZF1 and IKZF3 high-expression groups. Thus, the present results indicate that baicalein might be a therapeutic choice for targeting IKZF1 and IKZF3.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Flavanonas/farmacologia , Fator de Transcrição Ikaros/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/genética , Humanos , Fator de Transcrição Ikaros/metabolismo , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Análise de Sobrevida , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
14.
Int J Hematol ; 108(3): 312-318, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29786757

RESUMO

In this study, we performed genetic analysis of 83 B cell precursor acute lymphoblastic leukemia (B-ALL) cell lines. First, we performed multiplex ligation-dependent probe amplification analysis to identify copy number abnormalities (CNAs) in eight genes associated with B-ALL according to genetic subtype. In Ph+ B-ALL cell lines, the frequencies of IKZF1, CDKN2A/2B, BTG1, and PAX5 deletion were significantly higher than those in Ph- B-ALL cell lines. The frequency of CDKN2A/2B deletion in KMT2A rearranged cell lines was significantly lower than that in non-KMT2A rearranged cell lines. These findings suggest that CNAs are correlated with genetic subtype in B-ALL cell lines. In addition, we determined that three B-other ALL cell lines had IKZF1 deletions (YCUB-5, KOPN49, and KOPN75); we therefore performed comprehensive genetic analysis of these cell lines. YCUB-5, KOPN49, and KOPN75 had P2RY8-CRLF2, IgH-CRLF2, and PAX5-ETV6 fusions, respectively. Moreover, targeted capture sequencing revealed that YCUB-5 had JAK2 R683I and KRAS G12D, and KOPN49 had JAK2 R683G and KRAS G13D mutations. These data may contribute to progress in the field of leukemia research.


Assuntos
Variações do Número de Cópias de DNA/genética , Dosagem de Genes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Deleção de Genes , Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Fator de Transcrição Ikaros/genética , Janus Quinase 2/genética , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Proteínas Proto-Oncogênicas p21(ras)/genética
15.
Int J Lab Hematol ; 40(4): 427-436, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29575541

RESUMO

INTRODUCTION: Recent clinical outcomes of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) vastly improved owing to tyrosine kinase inhibitor (TKI). However, the genetic status would be different in each case with ABL1 gene mutation or copy number variants (CNVs) such as IKZF1 deletion. In particular, the TKI resistant clone with ABL1 kinase mutation remains problematic. The comprehensive assessment of genetic status including mutation, insertion and deletion (indel) and CNVs is necessary. METHODS: We evaluated a next-generation sequencing (NGS)-based customized HaloPlex target enrichment system panel to simultaneously detect coding mutations, indel and CNVs. We analysed approximately 160 known genes associated with hematological disorders in 5 pediatric Ph+ALL patients. RESULTS: Mono-allelic IKZF1 deletions were found in 4 patients at diagnosis. Furthermore, the mono-allelic deletions were found in exons of RB1, EBF1, PAX5 and ETV6 genes. Bi-allelic deletions were detected in CDKN2A and CDKN2B genes in 1 patient. ABL1 mutation was also detected in 1 patient at relapse. These results were almost comparable with the results of the multiplex ligation-dependent probe amplification (MLPA) method or Sanger sequence. CONCLUSION: Next-generation sequencing-based custom HaloPlex target enrichment system panel allows us to detect the coding mutations, indel, and CNVs in pediatric Ph+ALL simultaneously, and its results seem comparable with those of other methods.


Assuntos
Genes abl/genética , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Análise de Sequência de DNA/métodos , Adolescente , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Humanos , Mutação INDEL , Mutação , Deleção de Sequência
16.
Cell Physiol Biochem ; 45(5): 1787-1796, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29510406

RESUMO

BACKGROUND/AIMS: The IKZF3 gene encodes a zinc-finger protein that plays an important role in the proliferation and differentiation of B lymphocytes. Autoimmune thyroid diseases (AITDs), mainly include Graves' disease (GD) and Hashimoto's thyroiditis (HT), are probably caused by the aberrant proliferation of B cells. The objective of this study was to explore the association between IKZF3 polymorphisms and AITDs. METHODS: We examined 915 AITD patients (604 GD and 311 HT) and 814 healthy controls. IKZF3 variants (rs2941522, rs907091, rs1453559, rs12150079 and rs2872507) were tested by PCR-ligase detection reaction. RESULTS: It was manifested that that the minor alleles of the five loci increased susceptibility to GD (p<0.05 for rs2941522, and p<0.01 for rs907091, rs1453559, rs12150079 and rs2872507) but in HT patients, these loci showed no significant difference compared with controls. Similarly, the genotype distributions of GD patients manifested obvious differences in all these loci compared with the control group, whereas no statistical differences were observed between HT patients and controls. Furthermore, bioinformatics tools were used to analyze rs1453559, rs12150079 and rs907091. These variants were believed to be the transcription regulator. CONCLUSION: It is the first time we reported the association between the IKZF3 polymorphisms and GD, indicating that IKZF3 gene tends to bean important risk factor for the development of GD.


Assuntos
Doenças Autoimunes/genética , Doença de Graves/genética , Fator de Transcrição Ikaros/genética , Doenças da Glândula Tireoide/genética , Adulto , Alelos , Doenças Autoimunes/patologia , Sequência de Bases , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Doença de Graves/patologia , Doença de Hashimoto/genética , Doença de Hashimoto/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Doenças da Glândula Tireoide/patologia , Adulto Jovem
17.
Gene ; 647: 115-120, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29292192

RESUMO

Since two genome-wide association studies identified the same susceptible region at ARID5B and IKZF1 for acute leukemia in Caucasians in the same time, several research groups have confirmed the similar results in different ethnicities and of different acute leukemia subtypes (ALL and AML). However, the causal variants of these two genes were not identified. In this study, we systematically screened 6 potentially functional SNPs in ARID5B and IKZF1 genes, and conducted a case-control study including 660 AML cases and 1034 cancer-free controls to investigate the associations between these SNPs and AML risk. We found that the variant alleles of rs4509706 and rs11761922 could significantly increase the risk of AML (rs4509706: OR=1.35, 95%CI=1.12-1.62 in additive model; rs11761922: OR=1.29, 95%CI=1.02-1.62 in recessive model). Luciferase reporter assay showed that both rs11761922-G and rs4509706-C significantly increased the luciferase levels as compared with rs11761922-C and rs4509706-T in K562 cells (P<0.05 for rs11761922 and P<0.001 for rs4509706). Our results indicated that rs4509706 and rs11761922 may play important roles in AML development in Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Fator de Transcrição Ikaros/genética , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Adulto , Alelos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Células K562 , Masculino , Pessoa de Meia-Idade , Risco
18.
Sci Rep ; 8(1): 789, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335448

RESUMO

Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0-19 years) previously enrolled onto a Tokyo Children's Cancer Study Group trial were collected during 2013-2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10-17) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10-4) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10-6). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Fator de Transcrição Ikaros/genética , Lactente , Recém-Nascido , Japão , Desequilíbrio de Ligação , Masculino , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Adulto Jovem
19.
Diabetes ; 67(4): 697-703, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29343548

RESUMO

Although B cells reactive with islet autoantigens are silenced by tolerance mechanisms in healthy individuals, they can become activated and contribute to the development of type 1 diabetes. We previously demonstrated that high-affinity insulin-binding B cells (IBCs) occur exclusively in the anergic (BND) compartment in peripheral blood of healthy subjects. Consistent with their activation early in disease development, high-affinity IBCs are absent from the BND compartment of some first-degree relatives (FDRs) as well as all patients with autoantibody-positive prediabetes and new-onset type 1 diabetes, a time when they are found in pancreatic islets. Loss of BND IBCs is associated with a loss of the entire BND B-cell compartment consistent with provocation by an environmental trigger or predisposing genetic factors. To investigate potential mechanisms operative in subversion of B-cell tolerance, we explored associations between HLA and non-HLA type 1 diabetes-associated risk allele genotypes and loss of BNDs in FDRs. We found that high-risk HLA alleles and a subset of non-HLA risk alleles (i.e., PTPN2 [rs1893217], INS [rs689], and IKZF3 [rs2872507]), relevant to B- and T-cell development and function are associated with loss of anergy. Hence, the results suggest a role for risk-conferring alleles in perturbation of B-cell anergy during development of type 1 diabetes.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Anergia Clonal/imunologia , Diabetes Mellitus Tipo 1/imunologia , Estado Pré-Diabético/imunologia , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Humanos , Fator de Transcrição Ikaros/genética , Insulina/genética , Ilhotas Pancreáticas , Estado Pré-Diabético/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética
20.
Immunobiology ; 223(2): 252-257, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29107383

RESUMO

Ikaros is a broad transcription factor pointed as a critical regulator of lymphocyte development. Recent reports have emphasized that distinct isoforms of Ikaros control the dichotomy of the hematopoietic system into lymphoid and myeloid lineages. In addition, expression of dominant-negative isoforms of Ikaros is linked to abnormal hematopoiesis, which could culminate in hematological disorders due to loss of function of the protein. B-1 cells are an intriguing subtype of B-lymphocytes that preserves some myeloid characteristics. These cells are able to differentiate into phagocytes (B-1CDP - B-1 cell derived phagocytes) in vitro and in vivo. During such process, reprogramming of gene expression occurs: lymphoid genes are turned off, while expression of myeloid genes is increased. This study aims to investigate whether Ikaros could be related to the control of B-1 cell plasticity. Interestingly, Ikaros expression by B-1CDP cells was found to be relatively low, and the protein is abnormally localized in the cytoplasm. Moreover, the isoforms expressed by B-1 cells are different from those expressed by other lymphocytes, with expression of active isoforms being almost absent in B-1CDP. Based on these findings, Ikaros could be an important factor driving the differentiation and proliferation of B-1 cells.


Assuntos
Linfócitos B/imunologia , Fator de Transcrição Ikaros/metabolismo , Fagócitos/imunologia , Isoformas de Proteínas/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Plasticidade Celular , Células Cultivadas , Regulação da Expressão Gênica , Hematopoese , Fator de Transcrição Ikaros/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Isoformas de Proteínas/genética
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